All Around the Nose: Basic Science, Diseases and Surgical Management [1st ed. 2020] 978-3-030-21216-2, 978-3-030-21217-9

Table of contents :
Front Matter ....Pages i-xxvi
Introduction (Ranko Mladina)....Pages 1-20
Front Matter ....Pages 21-21
History of Rhinology (Cemal Cingi, Metin Onerci, Donald Leopold)....Pages 23-32
Histology and Embryology of the Nose and Paranasal Sinuses (İsa Azgın, Murat Kar, Emmanuel P. Prokopakis)....Pages 33-38
Surgical Anatomy of the External and Internal Nose (Engin Umut Sakarya, Murat Kar, Sameer Ali Bafaqeeh)....Pages 39-47
Surgical Anatomy of the Paranasal Sinuses (Yeşim Başal, Sema Başak, Jeffrey C. Bedrosian)....Pages 49-55
Physiology of the Nose and Paranasal Sinuses (Mehmet Emre Dinç, Nuray Bayar Muluk, Becky M. Vonakis)....Pages 57-63
Mucociliary Clearance and Its Importance (Deniz Tuna Edizer, Ozgur Yigit, Michael Rudenko)....Pages 65-70
Olfactory Function (Nihat Susaman, Aytuğ Altundağ, Philippe Rombaux)....Pages 71-74
Application of Computational Fluid Dynamics Methods to Understand Nasal Cavity Flows (Andreas Lintermann)....Pages 75-84
The Evaluation of the Nose, Nasal Cavity and Airway (Kazım Bozdemir, Hakan Korkmaz, Christine B. Franzese)....Pages 85-91
Clinical Assessment of Nasal Airway Obstruction (Ethem Sahin, Burak Çakır, Klaus Vogt)....Pages 93-100
Front Matter ....Pages 101-101
Clinical Assessment of Mucociliary Disorders (Uzdan Uz, Kıvanç Günhan, Noam Cohen)....Pages 103-108
Clinical Assessment of Olfactory Disorders (Tuğba Koçak, Aytuğ Altundağ, Thomas Hummel)....Pages 109-112
Acoustic Rhinometry (Erdem Atalay Çetinkaya, Mustafa Deniz Yılmaz, Nuray Bayar Muluk)....Pages 113-116
Principles of Allergy Skin Testing (Özlem Naciye Şahin, Cemal Cingi, Jennifer Derebery)....Pages 117-121
Nasal Provocation Tests (Duygu Zorlu, Nuray Bayar Muluk, Paloma Campo)....Pages 123-126
Radiologic Assessment of Nose and Paranasal Sinuses (Emre Gunbey, Pinar Gunbey, Pamela Nguyen)....Pages 127-147
Imaging of Nasal Cavity and Paranasal Sinus Tumors (Aslıhan Semiz Oysu, Nafi Aygün)....Pages 149-167
Front Matter ....Pages 169-169
Congenital Malformations of the Nose and Paranasal Sinuses (Ceren Günel, Sema Başak, Elina Toskala)....Pages 171-177
Superantigens and Biofilms in Sinus Diseases (Fazilet Altin, Husamettin Yasar, Martin Desrosiers)....Pages 179-185
Infantile Rhinitis (Ozge Yilmaz, Hasan Yuksel, Derya Altıntaş)....Pages 187-191
Microbiology of Rhinosinusitis and Antimicrobial Resistance (Nagehan Erdoğmuş Küçükcan, Sameer Ali Bafaqeeh, Suela Sallavaci)....Pages 193-197
Acute Viral Rhinitis (Tolgahan Çatlı, Huntürk Atilla, Eva Kathryn Miller)....Pages 199-202
Acute Bacterial Rhinosinusitis: Pediatric and Adult (Abdülkadir Imre, Sedat Ozturkcan, Livije Kalogjera)....Pages 203-211
Chronic Rhinosinusitis: Adults and Children (Ömer Çağatay Ertugay, Sema Zer Toros, Luo Zhang)....Pages 213-220
Complications of Rhinosinusitis (Duygu Erdem, Mitat Arıcıgil, Dennis Chua)....Pages 221-228
Acute Invasive Fungal Rhinosinusitis (Ahmet Emre Süslü, Oğuz Öğretmenoğlu, David W. Kennedy)....Pages 229-234
Allergic Fungal Rhinosinusitis (Sercan Göde, Bülent Karcı, Katharine Woessner)....Pages 235-237
Sinusitis and Chronic Progressive Exercise-Induced Cough and Dyspnea (Çiğdem Kalaycık Ertugay, Arzu Yorgancıoğlu, Ruby Pawankar)....Pages 239-246
Role of Anosmia on Personal Communication (Can Cemal Cingi, Erhan Eroglu, Gary Kreps)....Pages 247-251
Quality of Life in Rhinosinusitis (Selis Gülseven Güven, Muhsin Koten, Sheng-Po Hao)....Pages 253-257
Front Matter ....Pages 259-259
Pathophysiology of Allergic Rhinitis (Mehmet Emrah Ceylan, Cemal Cingi, Cevdet Özdemir, Umut Can Kücüksezer, Cezmi A. Akdis)....Pages 261-296
Epidemiology of Allergic Rhinitis (Ramazan Öçal, Nuray Bayar Muluk, Joaquim Mullol)....Pages 297-301
Hypersensitivity to Aspirin and Other Non-steroidal Anti-inflammatory Drugs (Adile Berna Dursun, Engin Dursun, D. Donald Stevenson)....Pages 303-310
Medical Treatment of Allergic Rhinitis (Emel Tahir, Cemal Cingi, Sarah K. Wise)....Pages 311-317
Immunotherapy for Allergic Rhinitis (Işıl Adadan Güvenç, Cemal Cingi, Glenis Scadding)....Pages 319-326
Herbal Remedy Alternatives for Allergic Rhinitis (Mehmet Emrah Ceylan, İhsan Kuzucu, Nuray Bayar Muluk)....Pages 327-331
Allergic Rhinitis in Pediatric Patients (Seçkin Ulusoy, Gülbin Bingol, Glenis Scadding)....Pages 333-342
Role of Allergic Rhinitis in Personal Communication (Can Cemal Cingi, Nezih Orhon, Petya Eckler)....Pages 343-345
Local Allergic Rhinitis (Baki Yılmaz, Cemal Cingi, William Reisacher)....Pages 347-352
Nonallergic Rhinitis (Asli Sahin-Yilmaz, Cagatay Oysu, Robert M. Naclerio)....Pages 353-363
Front Matter ....Pages 365-365
Epidemiology of Nasal Polyposis (Erkan Esen, Adin Selçuk, Desiderio Passali)....Pages 367-371
Pathophysiology of Chronic Rhinosinusitis with Nasal Polyps (Fatih Boztepe, Ahmet Ural, Gaetano Paludetti, Eugenio De Corso)....Pages 373-379
Medical Treatment of Nasal Polyposis (İhsan Kuzucu, İsmail Güler, Nuray Bayar Muluk)....Pages 381-386
Surgical Treatment of Nasal Polyposis (Şenol Çomoğlu, Nesil Keleş, James Palmer)....Pages 387-395
Evidence-Based Treatment on Nasal Polyposis (Bengü Çobanoğlu, Mehmet İmamoğlu, Luisa Bellussi)....Pages 397-404
Front Matter ....Pages 405-405
Paranasal Sinus Mucoceles (Oğuzhan Dikici, Nuray Bayar Muluk, Giulio Cesare Passali)....Pages 407-414
Management of Epistaxis (Kasım Durmuş, Emine Elif Altuntaş, Mario Milkov)....Pages 415-429
Rheumatological Diseases of the Nose and Paranasal Sinuses (Deniz Hancı, Yavuz Uyar, Ahmed El-Saggan)....Pages 431-440
Surgical Management of the Nasal Septum (Mehmet Özgür Pınarbaşlı, Hamdi Çaklı, Chae-Seo Rhee)....Pages 441-453
Nasal Valve Surgery (Mümtaz Taner Torun, İbrahim Çukurova, Andrey Lopatin)....Pages 455-460
Surgical Management of Septal Perforation (Elif Gülin Koçan, Demet Yazıcı, Abdelwahab Mahgoun)....Pages 461-467
Surgical Management of the Turbinates (Ercan Kaya, Erkan Özüdoğru, Joao Flavio Nogueira)....Pages 469-487
Odontogenic Causes of Sinus Infections (Burcu Çam, Oruç Yener Çam, Nuray Bayar Muluk)....Pages 489-497
Management of Trauma to the Nose and Paranasal Sinuses (İbrahim Çukurova, Murat Gümüşsoy, Peter Catalano)....Pages 499-507
Pediatric Septoplasty (Zerrin Özergin Coşkun, Engin Dursun, Charles M. Myer III, Douglas C. von Allmen)....Pages 509-523
Surgical Management of Choanal Atresia (İsmet Emrah Emre, Nuray Bayar Muluk, Milan Stankovic)....Pages 525-530
Tumors and Malignancies of the Nasal Cavity (Aylin Eryilmaz, Sema Başak, Hideyuki Kawauchi)....Pages 531-543
Robot-Assisted Surgery Around the Nose (Ayse Pelin Gör Yiğider, Fatma Tülin Kayhan)....Pages 545-551
Front Matter ....Pages 553-553
Minimally Invasive Endoscopic Sinus Surgery (Ozlem Onerci Celebi, Ozgur Yigit, Nicolas Busaba)....Pages 555-561
Functional Endoscopic Sphenoethmoidectomy (Tolgar Lütfi Kumral, Yavuz Uyar, Emmanuel P. Prokopakis)....Pages 563-569
Frontal Sinus Surgery (Ayça Özbal Koç, Selim Erbek, Gheorghe Mühlfay)....Pages 571-577
Complications of Endoscopic Sinus Surgery (Abdullah Durmaz, Mustafa Gerek)....Pages 579-585
Revision Sinus Surgery (Sercan Göde, Raşit Midilli, Stephan Vlaminck)....Pages 587-589
Dacryocystorhinostomy (İbrahim Çukurova, İlker Burak Arslan, Jivianne T. Lee)....Pages 591-596
Laser Dacryocystorhinostomy (Ela Araz Server, Ozgur Yigit, Stephan Lang)....Pages 597-603
Functional Endoscopic Dilatation of the Paranasal Sinuses (Demet Yazıcı, Osman Kürşat Arıkan, Jivianne T. Lee)....Pages 605-610
Endoscopic Sinus Surgery in Pediatric Patients (Cem Saka, Hakan Korkmaz, Tania Sih)....Pages 611-618
External Approaches for Sinus Surgery (Senem Kurt Dizdar, Berna Uslu Coşkun, Slobodan Spremo)....Pages 619-628
Combined Open and Endoscopic Approaches to the Paranasal Sinus (A. Volkan Sünter, Ozgur Yigit, Neven Skitarelic)....Pages 629-633
Endoscopic Management of Malignant Sinonasal Tumours (Erdoğan Özgür, Harun Üçüncü, Martin Jurlina)....Pages 635-641
Endoscopic Optic Nerve Decompression (Emel Çadallı Tatar, Hakan Korkmaz)....Pages 643-646
Endoscopic Management of Cerebrospinal Fluid Leaks and Encephaloceles (Umit Aydin, Mustafa Gerek, Sergei Karpischenko)....Pages 647-652
Endoscopic Transsphenoidal Hypophysectomy (Abdülkadir Imre, Ercan Pinar, Jeffrey Janus)....Pages 653-661
Endoscopic Skull Base Surgery: Anatomical Basis of Skull Base Approaches (M. Kürşat Gökcan, Süha Beton, Babur Küçük)....Pages 663-674
Conventional and Powered Instrumentation for Endoscopic Sinus Surgery (Recep Karamert, Fikret Ileri, Anthony Papavassiliou)....Pages 675-682
Conventional and Powered Instrumentation for Endoscopic Skull Base Surgery (Selçuk Mülazimoğlu, M. Kürşat Gökcan, Jacques Magnan)....Pages 683-692
Image-Guided Sinus Surgery (Mehmet Düzlü, Metin Yılmaz, Brent Senior)....Pages 693-697
3D Modeling Before Sinus Surgery (Fatih Oghan, Amr Osama, Hesham Negm)....Pages 699-704
Robotic Surgery of Skull Base (Alperen Vural, Hesham Negm, Claudio Vicini)....Pages 705-711
Front Matter ....Pages 713-713
Management of Small Nasal Defects (Ayse Pelin Gör Yiğider, Görkem Eskiizmir, Ali Reza Mesbahi)....Pages 715-724
Grafting in Nasal Reconstruction (Uzdan Uz, Görkem Eskiizmir, David Sherris)....Pages 725-735
Local Nasal Flaps (Gökçe Tanyeri Toker, Görkem Eskiizmir, Shan R. Baker)....Pages 737-746
Regional Nasal Flaps: Forehead Flaps (İbrahim Aladağ, Hale Arslan, Michael B. Soyka)....Pages 747-751
Inner Lining Reconstruction of the Nose (Mustafa Daloglu, Görkem Eskiizmir, Dmitry Zabolotny)....Pages 753-756
Management of Full-Thickness Nasal Defects (Kagan Ipci, Nuray Bayar Muluk, Gabriela Kopacheva-Barsova)....Pages 757-761
Regenerative Medicine in Rhinology (Kıvanç Günhan, Uzdan Uz)....Pages 763-767
Orthodontic Abnormalities of Upper Jaw as a Cause of Maxillary Sinus Problems (Oruç Yener Çam, Burcu Çam, Işıl Adadan Güvenç)....Pages 769-773
Front Matter ....Pages 775-775
Preoperative Facial Analysis (Erkan Eski, Cemal Cingi, Roxana Cobo)....Pages 777-782
Anesthesia for Rhinoplasty (Necdet Demir, Nuray Bayar Muluk, Peter Tomazic Velentin)....Pages 783-787
Endonasal and External Approaches in Rhinoplasty (Mehmet Akif Aksoy, Cemal Cingi, Norman Pastorek)....Pages 789-796
Basic Techniques for Endonasal Rhinoplasty (İsmail Güler, Işıl Adadan Güvenç, Gordon Soo)....Pages 797-808
Basıc Techniques for External Rhınoplasty (Gökçe Tanyeri Toker, Halis Unlu, Gilbert J. Nolst Trenité)....Pages 809-818
Osteotomies (Murat Songu, Cemal Cingi, Pietro Palma)....Pages 819-832
Management of the Mid-vault (Ahmet Biçer, Özge Bilkay, Ufuk Bilkay)....Pages 833-851
Management of the Deviated Septum (Ayşe Karaoğullarından, Joseph R. González, Andrew A. Winkler, Cemal Cingi)....Pages 853-859
Nasal Tip Surgery (Niyazi Altıntoprak, Cemal Cingi, Sameer Ali Bafaqeeh)....Pages 861-869
Alar Base Surgery (Bülent Koç, Nuray Bayar Muluk, Ji Yun Choi)....Pages 871-877
Reconstruction of Saddle Nose Deformity (Tolga Kırgezen, Ozgur Yigit, Dario Bertossi)....Pages 879-888
Complications of Rhinoplasty (Murat Kar, Cemal Cingi, Regan Thomas)....Pages 889-894
Revision Rhinoplasty (Seda Turkoglu Babakurban, Fuat Buyuklu, Jeffrey S. Moyer)....Pages 895-909
Rib Grafting In Rhinoplasty (Orhan Özturan, Berke Özücer, Wolfgang Gubish)....Pages 911-918
Allografts in Rhinoplasty (Denizhan Dizdar, Seçkin Ulusoy, Hong Ryul Jin)....Pages 919-921
Application of Fillers in Nonsurgical Rhinoplasty (Emine Güven Şakalar, Cemal Cingi, Oren Friedman)....Pages 923-929
Communication Disorders Due to Facial Deformities (Can Cemal Cingi, Erkan Yüksel, Ola Omar Shahin)....Pages 931-936

Citation preview

Cemal Cingi Nuray Bayar Muluk Editors

All Around the Nose Basic Science, Diseases and Surgical Management

123

All Around the Nose

Cemal Cingi  •  Nuray Bayar Muluk Editors

All Around the Nose Basic Science, Diseases and Surgical Management

Editors Cemal Cingi Eskişehir Osmangazi University Medical Faculty Department of Otorhinolaryngology Eskisehir Turkey

Nuray Bayar Muluk Department of Otorhinolaryngology Medical Faculty, Kirikkale University Kirikkale Turkey

ISBN 978-3-030-21216-2    ISBN 978-3-030-21217-9 (eBook) https://doi.org/10.1007/978-3-030-21217-9 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

“All Around the Nose”

Whenever we glance at someone’s face during interpersonal communication, we look directly at the eyes. The reason is that it is only the eyes that are able to reveal meaning and offer clues about the feelings of another person. Yet, although it is indeed the eyes we first look at, we also simultaneously see the nose, even at the first quick glance, because it is found right in the middle of the face and lingers within our visual field. So, the nose might truly be considered the most important and prominent part of the face. Quite apart from its key location on the face, the nose plays an essential part in our quality of life as the very starting point of that most vital of activities: breathing. Granted, we may breathe through our mouths on occasion, but I am sure everybody knows the dreadful feelings produced by a stuffy nose, even when the only reason for it is a flu-like illness that we are sure will end within a few days. Throughout my career in ENT, I have always liked doing functional and cosmetic surgery on the nose. It gives me the chance to show and share my artistic vision with my patients and everybody else through the surgical outcome, quite unlike middle ear or laryngeal surgery, where all our efforts remain hidden at the end of the surgical procedure. Many methods and sutures have been described for rhinoplasty surgery, but how the actual procedure is performed depends on using the surgeon’s imagination to plan, and the surgeon’s hands to realize, that vision. So there is always a personal value added to the final outcome. Likewise, in this volume, we have all endeavored to enrich previously published classical information on the subject, with our own personal take, drawn from experience of putting that information into use. As ENT and facial plastic surgeons, we deal not only with the nose itself but also with the many problems all around the nose. That is why we decided to entitle this comprehensive textbook All Around the Nose. This rhinology book is designed to include all the major aspects of nasal and paranasal sinus disease and the current treatment modalities. It was planned to be the collaboration of 280 authors, both senior and more junior, and involve the contributions of many world-renowned leaders in the field. Initially, in most cases, the chapters were drafted by our junior authors from Turkey. They have provided fundamental and basic information together with updates and some more esoteric knowledge on each subject. As a second step, all the draft chapters have been meticulously reviewed and further improved by the second authors. As the final step, we solicited contributions from many world-renowned experts for a final review and the addition of some last-minute touches. As a matter of fact, their professional experiences and personal messages have made a lasting contribution to this textbook. I would like to thank all our authors for their many valuable contributions. My special thanks go to Nuray Bayar Muluk, who worked tirelessly for this project as a writer and coeditor. Without her endless patience, intelligence, and support, this book might never have reached its final form. I would like to end with a wish that this work may be of help to all its readers, wherever they come from and whatever their level of previous experience may be. Eskisehir, Turkey March, 2018

Cemal Cingi

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Contents

1 Introduction���������������������������������������������������������������������������������������������������������������   1 Ranko Mladina



Part I Basic Science of Nose and Paranasal Sinuses 2 History of Rhinology�������������������������������������������������������������������������������������������������  23 Cemal Cingi, Metin Onerci, and Donald Leopold 3 Histology and Embryology of the Nose and Paranasal Sinuses���������������������������  33 İsa Azgın, Murat Kar, and Emmanuel P. Prokopakis 4 Surgical Anatomy of the External and Internal Nose�������������������������������������������  39 Engin Umut Sakarya, Murat Kar, and Sameer Ali Bafaqeeh 5 Surgical Anatomy of the Paranasal Sinuses�����������������������������������������������������������  49 Yeşim Başal, Sema Başak, and Jeffrey C. Bedrosian 6 Physiology of the Nose and Paranasal Sinuses�������������������������������������������������������  57 Mehmet Emre Dinç, Nuray Bayar Muluk, and Becky M. Vonakis



7 Mucociliary Clearance and Its Importance�����������������������������������������������������������  65 Deniz Tuna Edizer, Ozgur Yigit, and Michael Rudenko 8 Olfactory Function���������������������������������������������������������������������������������������������������  71 Nihat Susaman, Aytuğ Altundağ, and Philippe Rombaux 9 Application of Computational Fluid Dynamics Methods to Understand Nasal Cavity Flows �������������������������������������������������������������������������  75 Andreas Lintermann 10 The Evaluation of the Nose, Nasal Cavity and Airway�����������������������������������������  85 Kazım Bozdemir, Hakan Korkmaz, and Christine B. Franzese 11 Clinical Assessment of Nasal Airway Obstruction�������������������������������������������������  93 Ethem Sahin, Burak Çakır, and Klaus Vogt Part II Assessment of Nose and Paranasal Sinuses 12 Clinical Assessment of Mucociliary Disorders������������������������������������������������������� 103 Uzdan Uz, Kıvanç Günhan, and Noam Cohen 13 Clinical Assessment of Olfactory Disorders����������������������������������������������������������� 109 Tuğba Koçak, Aytuğ Altundağ, and Thomas Hummel 14 Acoustic Rhinometry ����������������������������������������������������������������������������������������������� 113 Erdem Atalay Çetinkaya, Mustafa Deniz Yılmaz, and Nuray Bayar Muluk

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15 Principles of Allergy Skin Testing��������������������������������������������������������������������������� 117 Özlem Naciye Şahin, Cemal Cingi, and Jennifer Derebery 16 Nasal Provocation Tests ������������������������������������������������������������������������������������������� 123 Duygu Zorlu, Nuray Bayar Muluk, and Paloma Campo 17 Radiologic Assessment of Nose and Paranasal Sinuses����������������������������������������� 127 Emre Gunbey, Pinar Gunbey, and Pamela Nguyen 18 Imaging of Nasal Cavity and Paranasal Sinus Tumors����������������������������������������� 149 Aslıhan Semiz Oysu and Nafi Aygün Part III Diseases of the Nose and Paranasal Sinuses 19 Congenital Malformations of the Nose and Paranasal Sinuses ��������������������������� 171 Ceren Günel, Sema Başak, and Elina Toskala 20 Superantigens and Biofilms in Sinus Diseases������������������������������������������������������� 179 Fazilet Altin, Husamettin Yasar, and Martin Desrosiers 21 Infantile Rhinitis������������������������������������������������������������������������������������������������������� 187 Ozge Yilmaz, Hasan Yuksel, and Derya Altıntaş 22 Microbiology of Rhinosinusitis and Antimicrobial Resistance����������������������������� 193 Nagehan Erdoğmuş Küçükcan, Sameer Ali Bafaqeeh, and Suela Sallavaci 23 Acute Viral Rhinitis ������������������������������������������������������������������������������������������������� 199 Tolgahan Çatlı, Huntürk Atilla, and Eva Kathryn Miller 24 Acute Bacterial Rhinosinusitis: Pediatric and Adult��������������������������������������������� 203 Abdülkadir Imre, Sedat Ozturkcan, and Livije Kalogjera 25 Chronic Rhinosinusitis: Adults and Children ������������������������������������������������������� 213 Ömer Çağatay Ertugay, Sema Zer Toros, and Luo Zhang 26 Complications of Rhinosinusitis ����������������������������������������������������������������������������� 221 Duygu Erdem, Mitat Arıcıgil, and Dennis Chua 27 Acute Invasive Fungal Rhinosinusitis��������������������������������������������������������������������� 229 Ahmet Emre Süslü, Oğuz Öğretmenoğlu, and David W. Kennedy 28 Allergic Fungal Rhinosinusitis��������������������������������������������������������������������������������� 235 Sercan Göde, Bülent Karcı, and Katharine Woessner 29 Sinusitis and Chronic Progressive Exercise-Induced Cough and Dyspnea��������� 239 Çiğdem Kalaycık Ertugay, Arzu Yorgancıoğlu, and Ruby Pawankar 30 Role of Anosmia on Personal Communication������������������������������������������������������� 247 Can Cemal Cingi, Erhan Eroglu, and Gary Kreps 31 Quality of Life in Rhinosinusitis����������������������������������������������������������������������������� 253 Selis Gülseven Güven, Muhsin Koten, and Sheng-Po Hao Part IV Allergic and Non-allergic Rhinitis 32 Pathophysiology of Allergic Rhinitis����������������������������������������������������������������������� 261 Mehmet Emrah Ceylan, Cemal Cingi, Cevdet Özdemir, Umut Can Kücüksezer, and Cezmi A. Akdis 33 Epidemiology of Allergic Rhinitis��������������������������������������������������������������������������� 297 Ramazan Öçal, Nuray Bayar Muluk, and Joaquim Mullol

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34 Hypersensitivity to Aspirin and Other Non-steroidal Anti-inflammatory Drugs����������������������������������������������������������������������������������������� 303 Adile Berna Dursun, Engin Dursun, and D. Donald Stevenson 35 Medical Treatment of Allergic Rhinitis������������������������������������������������������������������� 311 Emel Tahir, Cemal Cingi, and Sarah K. Wise 36 Immunotherapy for Allergic Rhinitis��������������������������������������������������������������������� 319 Işıl Adadan Güvenç, Cemal Cingi, and Glenis Scadding 37 Herbal Remedy Alternatives for Allergic Rhinitis������������������������������������������������� 327 Mehmet Emrah Ceylan, İhsan Kuzucu, and Nuray Bayar Muluk 38 Allergic Rhinitis in Pediatric Patients��������������������������������������������������������������������� 333 Seçkin Ulusoy, Gülbin Bingol, and Glenis Scadding 39 Role of Allergic Rhinitis in Personal Communication������������������������������������������� 343 Can Cemal Cingi, Nezih Orhon, and Petya Eckler 40 Local Allergic Rhinitis ��������������������������������������������������������������������������������������������� 347 Baki Yılmaz, Cemal Cingi, and William Reisacher 41 Nonallergic Rhinitis ������������������������������������������������������������������������������������������������� 353 Asli Sahin-Yilmaz, Cagatay Oysu, and Robert M. Naclerio Part V Nasal Polyposis 42 Epidemiology of Nasal Polyposis����������������������������������������������������������������������������� 367 Erkan Esen, Adin Selçuk, and Desiderio Passali 43 Pathophysiology of Chronic Rhinosinusitis with Nasal Polyps����������������������������� 373 Fatih Boztepe, Ahmet Ural, Gaetano Paludetti, and Eugenio De Corso 44 Medical Treatment of Nasal Polyposis ������������������������������������������������������������������� 381 İhsan Kuzucu, İsmail Güler, and Nuray Bayar Muluk 45 Surgical Treatment of Nasal Polyposis������������������������������������������������������������������� 387 Şenol Çomoğlu, Nesil Keleş, and James Palmer 46 Evidence-Based Treatment on Nasal Polyposis ����������������������������������������������������� 397 Bengü Çobanoğlu, Mehmet İmamoğlu, and Luisa Bellussi Part VI Surgery of Nasal Cavity and Airway 47 Paranasal Sinus Mucoceles ������������������������������������������������������������������������������������� 407 Oğuzhan Dikici, Nuray Bayar Muluk, and Giulio Cesare Passali 48 Management of Epistaxis����������������������������������������������������������������������������������������� 415 Kasım Durmuş, Emine Elif Altuntaş, and Mario Milkov 49 Rheumatological Diseases of the Nose and Paranasal Sinuses����������������������������� 431 Deniz Hancı, Yavuz Uyar, and Ahmed El-Saggan 50 Surgical Management of the Nasal Septum����������������������������������������������������������� 441 Mehmet Özgür Pınarbaşlı, Hamdi Çaklı, and Chae-Seo Rhee 51 Nasal Valve Surgery ������������������������������������������������������������������������������������������������� 455 Mümtaz Taner Torun, İbrahim Çukurova, and Andrey Lopatin 52 Surgical Management of Septal Perforation ��������������������������������������������������������� 461 Elif Gülin Koçan, Demet Yazıcı, and Abdelwahab Mahgoun

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53 Surgical Management of the Turbinates����������������������������������������������������������������� 469 Ercan Kaya, Erkan Özüdoğru, and Joao Flavio Nogueira 54 Odontogenic Causes of Sinus Infections����������������������������������������������������������������� 489 Burcu Çam, Oruç Yener Çam, and Nuray Bayar Muluk 55 Management of Trauma to the Nose and Paranasal Sinuses ������������������������������� 499 İbrahim Çukurova, Murat Gümüşsoy, and Peter Catalano 56 Pediatric Septoplasty ����������������������������������������������������������������������������������������������� 509 Zerrin Özergin Coşkun, Engin Dursun, Charles M. Myer III, and Douglas C. von Allmen 57 Surgical Management of Choanal Atresia ������������������������������������������������������������� 525 İsmet Emrah Emre, Nuray Bayar Muluk, and Milan Stankovic 58 Tumors and Malignancies of the Nasal Cavity������������������������������������������������������� 531 Aylin Eryilmaz, Sema Başak, and Hideyuki Kawauchi 59 Robot-Assisted Surgery Around the Nose ������������������������������������������������������������� 545 Ayse Pelin Gör Yiğider and Fatma Tülin Kayhan Part VII Surgical Management of Paranasal Sinuses 60 Minimally Invasive Endoscopic Sinus Surgery ����������������������������������������������������� 555 Ozlem Onerci Celebi, Ozgur Yigit, and Nicolas Busaba 61 Functional Endoscopic Sphenoethmoidectomy����������������������������������������������������� 563 Tolgar Lütfi Kumral, Yavuz Uyar, and Emmanuel P. Prokopakis 62 Frontal Sinus Surgery����������������������������������������������������������������������������������������������� 571 Ayça Özbal Koç, Selim Erbek, and Gheorghe Mühlfay 63 Complications of Endoscopic Sinus Surgery��������������������������������������������������������� 579 Abdullah Durmaz and Mustafa Gerek 64 Revision Sinus Surgery��������������������������������������������������������������������������������������������� 587 Sercan Göde, Raşit Midilli, and Stephan Vlaminck 65 Dacryocystorhinostomy ������������������������������������������������������������������������������������������� 591 İbrahim Çukurova, İlker Burak Arslan, and Jivianne T. Lee 66 Laser Dacryocystorhinostomy��������������������������������������������������������������������������������� 597 Ela Araz Server, Ozgur Yigit, and Stephan Lang 67 Functional Endoscopic Dilatation of the Paranasal Sinuses��������������������������������� 605 Demet Yazıcı, Osman Kürşat Arıkan, and Jivianne T. Lee 68 Endoscopic Sinus Surgery in Pediatric Patients ��������������������������������������������������� 611 Cem Saka, Hakan Korkmaz, and Tania Sih 69 External Approaches for Sinus Surgery����������������������������������������������������������������� 619 Senem Kurt Dizdar, Berna Uslu Coşkun, and Slobodan Spremo 70 Combined Open and Endoscopic Approaches to the Paranasal Sinus ��������������� 629 A. Volkan Sünter, Ozgur Yigit, and Neven Skitarelic 71 Endoscopic Management of Malignant Sinonasal Tumours��������������������������������� 635 Erdoğan Özgür, Harun Üçüncü, and Martin Jurlina

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72 Endoscopic Optic Nerve Decompression ��������������������������������������������������������������� 643 Emel Çadallı Tatar and Hakan Korkmaz 73 Endoscopic Management of Cerebrospinal Fluid Leaks and Encephaloceles��������������������������������������������������������������������������������������������������� 647 Umit Aydin, Mustafa Gerek, and Sergei Karpischenko 74 Endoscopic Transsphenoidal Hypophysectomy����������������������������������������������������� 653 Abdülkadir Imre, Ercan Pinar, and Jeffrey Janus 75 Endoscopic Skull Base Surgery: Anatomical Basis of Skull Base Approaches������������������������������������������������������������������������������������������������������� 663 M. Kürşat Gökcan, Süha Beton, and Babur Küçük 76 Conventional and Powered Instrumentation for Endoscopic Sinus Surgery ����������������������������������������������������������������������������������������������������������� 675 Recep Karamert, Fikret Ileri, and Anthony Papavassiliou 77 Conventional and Powered Instrumentation for Endoscopic Skull Base Surgery��������������������������������������������������������������������������������������������������� 683 Selçuk Mülazimoğlu, M. Kürşat Gökcan, and Jacques Magnan 78 Image-Guided Sinus Surgery����������������������������������������������������������������������������������� 693 Mehmet Düzlü, Metin Yılmaz, and Brent Senior 79 3D Modeling Before Sinus Surgery������������������������������������������������������������������������� 699 Fatih Oghan, Amr Osama, and Hesham Negm 80 Robotic Surgery of Skull Base��������������������������������������������������������������������������������� 705 Alperen Vural, Hesham Negm, and Claudio Vicini Part VIII Nasal Reconstruction 81 Management of Small Nasal Defects����������������������������������������������������������������������� 715 Ayse Pelin Gör Yiğider, Görkem Eskiizmir, and Ali Reza Mesbahi 82 Grafting in Nasal Reconstruction��������������������������������������������������������������������������� 725 Uzdan Uz, Görkem Eskiizmir, and David Sherris 83 Local Nasal Flaps ����������������������������������������������������������������������������������������������������� 737 Gökçe Tanyeri Toker, Görkem Eskiizmir, and Shan R. Baker 84 Regional Nasal Flaps: Forehead Flaps������������������������������������������������������������������� 747 İbrahim Aladağ, Hale Arslan, and Michael B. Soyka 85 Inner Lining Reconstruction of the Nose��������������������������������������������������������������� 753 Mustafa Daloglu, Görkem Eskiizmir, and Dmitry Zabolotny 86 Management of Full-Thickness Nasal Defects������������������������������������������������������� 757 Kagan Ipci, Nuray Bayar Muluk, and Gabriela Kopacheva-Barsova 87 Regenerative Medicine in Rhinology���������������������������������������������������������������������� 763 Kıvanç Günhan and Uzdan Uz 88 Orthodontic Abnormalities of Upper Jaw as a Cause of Maxillary Sinus Problems����������������������������������������������������������������������������������� 769 Oruç Yener Çam, Burcu Çam, and Işıl Adadan Güvenç

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Part IX Rhinoplasty 89 Preoperative Facial Analysis ����������������������������������������������������������������������������������� 777 Erkan Eski, Cemal Cingi, and Roxana Cobo 90 Anesthesia for Rhinoplasty ������������������������������������������������������������������������������������� 783 Necdet Demir, Nuray Bayar Muluk, and Peter Tomazic Velentin 91 Endonasal and External Approaches in Rhinoplasty ������������������������������������������� 789 Mehmet Akif Aksoy, Cemal Cingi, and Norman Pastorek 92 Basic Techniques for Endonasal ­Rhinoplasty��������������������������������������������������������� 797 İsmail Güler, Işıl Adadan Güvenç, and Gordon Soo 93 Basıc Techniques for External ­Rhınoplasty����������������������������������������������������������� 809 Gökçe Tanyeri Toker, Halis Unlu, and Gilbert J. Nolst Trenité 94 Osteotomies��������������������������������������������������������������������������������������������������������������� 819 Murat Songu, Cemal Cingi, and Pietro Palma 95 Management of the Mid-vault��������������������������������������������������������������������������������� 833 Ahmet Biçer, Özge Bilkay, and Ufuk Bilkay 96 Management of the Deviated Septum��������������������������������������������������������������������� 853 Ayşe Karaoğullarından, Joseph R. González, Andrew A. Winkler, and Cemal Cingi 97 Nasal Tip Surgery����������������������������������������������������������������������������������������������������� 861 Niyazi Altıntoprak, Cemal Cingi, and Sameer Ali Bafaqeeh 98 Alar Base Surgery����������������������������������������������������������������������������������������������������� 871 Bülent Koç, Nuray Bayar Muluk, and Ji Yun Choi 99 Reconstruction of Saddle Nose Deformity ������������������������������������������������������������� 879 Tolga Kırgezen, Ozgur Yigit, and Dario Bertossi 100 Complications of Rhinoplasty��������������������������������������������������������������������������������� 889 Murat Kar, Cemal Cingi, and Regan Thomas 101 Revision Rhinoplasty ����������������������������������������������������������������������������������������������� 895 Seda Turkoglu Babakurban, Fuat Buyuklu, and Jeffrey S. Moyer 102 Rib Grafting In Rhinoplasty ����������������������������������������������������������������������������������� 911 Orhan Özturan, Berke Özücer, and Wolfgang Gubish 103 Allografts in Rhinoplasty����������������������������������������������������������������������������������������� 919 Denizhan Dizdar, Seçkin Ulusoy, and Hong Ryul Jin 104 Application of Fillers in Nonsurgical ­Rhinoplasty������������������������������������������������� 923 Emine Güven Şakalar, Cemal Cingi, and Oren Friedman 105 Communication Disorders Due to Facial Deformities������������������������������������������� 931 Can Cemal Cingi, Erkan Yüksel, and Ola Omar Shahin

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About the Editors

Cemal Cingi, MD  is a Professor in the Otorhinolaryngology Department at Eskisehir Osmangazi University, Medical Faculty, Eskisehir, Turkey. He graduated from the School of Medicine, Istanbul University, in 1984 and then entered the Otorhinolaryngology Residency Programme at Anadolu University, Eskisehir, becoming a Specialist in ORL and HNS in 1990. He was appointed as an Associate Professor in 1995 and as a Professor in 2000. In 2013, he became an Accredited Specialist in mouth, face, and chin surgery. He was the Chair of the ENT Section of the European Academy of Allergy and Clinical Immunology (EAACI) and President of the Asian Facial Plastic Surgery Society (AFPSS). He has more than 250 published papers. He is Editor of the journal ENT Updates and an Editorial Board Member for several other journals. He is the Author or Editor of eight previous books. Nuray  Bayar Muluk, MD  is a Professor in the Otorhinolaryngology Department at Kirikkale University, Medical Faculty, in Turkey. She graduated from Hacettepe University, Faculty of Medicine, in 1990 and completed her ENT residency there in 1994. She became Assistant Professor in 1997, Associate Professor in 2003, and Professor in 2008 in Kırıkkale University, Faculty of Medicine, ENT Department. Her special interests are basic research, rhinology, and allergy. She has 210 international publications, 70 national publications, an international book, a national book, 5 international book chapters, 43 national book chapters, and 11 translation book chapters. She has 500 citations in international journals covered by Web of Science.

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Contributors

Cezmi A. Akdis, MD  Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland Mehmet Akif Aksoy, MD  Private Sevgi Hospital, Ordu, Turkey İbrahim Aladağ, MD  Department of Otorhinolaryngology, Atatürk Training and Research Hospital, İzmir Katip Çelebi University, İzmir, Turkey ENT Department, Atatürk Training and Research Hospital, İzmir Katip Çelebi University, İzmir, Turkey Fazilet  Altin, MD Department of Otorhinolaryngology, University of Health Sciences, Haseki Training and Research Hospital, Istanbul, Turkey Derya Altıntaş, MD  Department of Pediatric Allergy, Medical Faculty, Çukurova University, Adana, Turkey Niyazi Altıntoprak, MD  Department of Otorhinolaryngology, Medical Park Gebze Hospital, Gebze, Kocaeli, Turkey Aytuğ Altundağ, MD  Istanbul Smell and Taste Center, Polat Tower, Istanbul, Turkey Emine Elif Altuntaş, MD  Medical Faculty, Department of Otorhinolaryngology, Cumhuriyet University, Sivas, Turkey Mitat  Arıcıgil, MD Department of Otorhinolaryngology, Medical Faculty, Necmettin Erbakan University, Konya, Turkey Osman  Kürşat  Arıkan, MD Department of Otorhinolaryngology, University of Health Sciences, Adana Numune Training and Research Hospital, Adana, Turkey Hale  Arslan, MD Department of Otorhinolaryngology, Atatürk Training and Research Hospital, İzmir Katip Çelebi University, İzmir, Turkey ENT Department, Atatürk Training and Research Hospital, İzmir Katip Çelebi University, İzmir, Turkey İlker Burak Arslan, MD  Department of Otorhinolaryngology, University of Health Sciences, Tepecik Training and Research Hospital, İzmir, Turkey Huntürk  Atilla, MD Department of Otorhinolaryngology, University of Health Sciences, Yenimahalle Training and Research Hospital, Ankara, Turkey Umit  Aydin, MD Department of Otorhinolaryngology, University of Health Sciences, Gülhane Medical School, Ankara, Turkey Nafi Aygün, MD  Division of Neuroradiology, Russel H. Morgan Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, USA

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İsa Azgın, MD  Department of Otorhinolaryngology, University of Health Sciences, Konya Training and Research Hospital, Konya, Turkey Seda  Turkoglu  Babakurban, MD, PhD Department of Otorhinolaryngology, Başkent University Faculty of Medicine, Ankara, Turkey Sameer  Ali  Bafaqeeh, MD Facial Plastic Division, Department of Otolaryngology, King Saud University, Riyadh, Saudi Arabia Shan R. Baker, MD  Department of Otolayngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA Sema  Başak, MD  Department of Otorhinolaryngology, Medical Faculty, Adnan Menderes University, Aydın, Turkey Yeşim  Başal, MD  Department of Otorhinolaryngology, Medical Faculty, Adnan Menderes University, Aydın, Turkey Jeffrey C. Bedrosian, MD  Rhinology and Skull Base Surgery, Specialty Physician Associates, St. Luke’s Medical Centre, Bethlehem, PA, USA Luisa Bellussi, MD  Medical Faculty, Department of Otorhinolaryngology—Head and Neck Surgery, University of Siena, Siena, Italy Dario Bertossi, MD  Maxillo Facial Surgery Department, University of Verona, Verona, Italy Süha Beton, MD  Medical Faculty, Department of Otorhinolaryngology, Ankara University, Ankara, Turkey Ahmet Biçer, MD  Faculty of Medicine, Department of Plastic, Reconstructive, and Aesthetic Surgery, Ege University, İzmir, Turkey Özge  Bilkay, MD Department of Otorhinolaryngology, Alsancak State Hospital, İzmir, Turkey Ufuk Bilkay, MD  Faculty of Medicine, Department of Plastic, Reconstructive, and Aesthetic Surgery, Ege University, İzmir, Turkey Gülbin Bingol, MD  Medical Faculty, Pediatric Allergy Department, Acıbadem Mehmet Ali Aydınlar, Istanbul, Turkey Kazım  Bozdemir, MD Department of Otorhinolaryngology, Medical Faculty, Yıldırım Beyazıt University, Ankara, Turkey Fatih  Boztepe, MD Department of Otorhinolaryngology, Antalya Medical Park Hospital, Antalya, Turkey Nicolas  Busaba, MD Department of Otorhinolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA Fuat  Buyuklu, MD Department of Otorhinolaryngology, Baskent University Faculty of Medicine, Ankara, Turkey Burak Çakır, MD  Department of Otorhinolaryngology, Beykent University, İstanbul, Turkey Hamdi  Çaklı, MD Medical Faculty, Department of Otorhinolaryngology, Eskişehir Osmangazi University, Eskişehir, Turkey Burcu Çam, PhD, DDS  Department of Oral and Maxillofacial Surgery, Adana Fatma Kemal Timuçin Oral and Dental Health Hospital, Adana, Turkey Oruç Yener Çam, PhD, DDS  Department of Orthodontics, Faculty of Dentistry, Çukurova University, Adana, Turkey

Contributors

Contributors

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Paloma  Campo, MD Allergy Unit, IBIMA-Hospital Regional Universitario de Málaga, ARADyAL, Madrid, Spain Peter  Catalano, MD, FACS, FARS Department of Otorhinolaryngology, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA, USA Tolgahan  Çatlı, MD Department of Otorhinolaryngology, University of Health Sciences, Bozyaka Training and Research Hospital, İzmir, Turkey Ozlem  Onerci Celebi, MD Department of Otorhinolaryngology, University of Health Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey Erdem  Atalay  Çetinkaya, MD  Department of Otorhinolaryngology, University of Health Sciences, Antalya Training and Research Hospital, Antalya, Turkey Mehmet Emrah Ceylan, MD  Department of Otorhinolaryngology, Davraz Yaşam Hospital, Isparta, Turkey Ji Yun Choi, MD, PhD  Department of Otorhinolaryngology, Chosun University Hospital and College of Medicine, Seoul, South Korea Dennis Chua, MD  ENT Surgeons Medical Centre, Singapore, Singapore Can Cemal Cingi, PhD  Faculty of Communication Sciences, Anadolu University, Eskisehir, Turkey Cemal  Cingi, MD Eskişehir Osmangazi University, Medical Faculty, Department of Otorhinolaryngology, Eskisehir, Turkey Bengü  Çobanoğlu, MD Medical Faculty, Department of Otorhinolaryngology, Karadeniz Technical University, Trabzon, Turkey Roxana Cobo, MD  Division of Facial Plastic Surgery, Department of Otolaryngology, Centro Medico Imbanaco, Cali, Colombia Noam Cohen, MD  Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Şenol  Çomoğlu, MD Istanbul Faculty of Medicine, Department of Otorhinolaryngology, Istanbul University, Istanbul, Turkey Berna Uslu Coşkun, MD  Department of Otorhinolaryngology, University of Health Sciences, Şişli Etfal Training and Research Hospital, Istanbul, Turkey Zerrin Özergin Coşkun, MD  Department of Otolaryngology Head and Neck Surgery, Recep Tayyip Erdoğan University, Medical Faculty, Rize, Turkey İbrahim Çukurova, MD  Department of Otorhinolaryngology, University of Health Sciences, Tepecik Training and Research Hospital, İzmir, Turkey Mustafa  Daloglu, MD Department of Medical Education, Akdeniz University, Antalya, Turkey Eugenio De Corso, MD  Agostino Gemelli Hospital Foundation, Catholic University of the Sacred Heart, Head and Neck Surgery Area, Institute of Otorhinolaryngology, Rome, Italy Necdet Demir, MD  ENT Department, VM Medicalpark Pendik Hospital, Istanbul, Turkey Jennifer  Derebery, MD, FACS Department of Otolaryngology-Head and Neck Surgery, House Ear Clinic and Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA Martin Desrosiers, MD, FRCSC  Department of Otorhinolaryngology, Montreal University, Center Hospital, Montreal, QC, Canada

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Oğuzhan  Dikici, MD  Department of Otorhinolaryngology, Bursa Yüksek Ihtisas Training and Research Hospital, Bursa, Turkey Mehmet  Emre  Dinç, MD Department of Otorhinolaryngology, Okmeydanı Training and Research Hospital, University of Health Sciences, İstanbul, Turkey Denizhan Dizdar, MD  Medical Faculty, Department of Otorhinolaryngology, Medical Park Bahçelievler Hospital, İstinye University, Istanbul, Turkey Senem Kurt Dizdar, MD  Department of Otorhinolaryngology, University of Health Sciences, Şişli Etfal Training and Research Hospital, Istanbul, Turkey Abdullah  Durmaz, MD Department of Otorhinolaryngology, Gülhane Medical School, University of Health Sciences, Ankara, Turkey Kasım  Durmuş, MD Medical Faculty, Department of Otorhinolaryngology, Cumhuriyet University, Sivas, Turkey Adile  Berna  Dursun, MD Division of Immunology and Allergic Diseases, School of Medicine, Recep Tayyip Erdogan University, Rize, Turkey Engin Dursun, MD  Department of Otorhinolaryngology, School of Medicine, Recep Tayyip Erdogan University, Rize, Turkey Mehmet Düzlü, MD  Faculty of Medicine, Otorhinolaryngology Department, Gazi University, Ankara, Turkey Petya Eckler, PhD  School of Humanities, University of Strathclyde, Glasgow, UK Deniz Tuna Edizer, MD  Department of Otorhinolaryngology, University of Health Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey Ahmed  El-Saggan, MD Department of ENT, Stavanger University Hospital, Stavanger, Norway İsmet  Emrah  Emre, MD Department of Otorhinolaryngology, Acıbadem Mehmet Ali Aydınlar Medical Faculty, İstanbul, Turkey Selim Erbek, MD  Department of Otorhinolaryngology, Medical Faculty, Baskent University, Ankara, Turkey Duygu Erdem, MD  Department of Otorhinolaryngology, Medical Faculty, Zonguldak Bülent Ecevit University, Zonguldak, Turkey Erhan  Eroglu, PhD Faculty of Communication Sciences, Anadolu University, Eskisehir, Turkey Çiğdem Kalaycık Ertugay, MD  Department of Otorhinolaryngology, University of Health Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey Ömer  Çağatay  Ertugay, MD Department of Otorhinolaryngology, University of Health Sciences, Haydarpaşa Numune Training and Research Hospital, Istanbul, Turkey Aylin Eryilmaz, MD  Department of Otorhinolaryngology, Medical Faculty, Adnan Menderes University, Aydın, Turkey Erkan  Esen, MD Department of Otorhinolaryngology, University of Health Sciences, Kocaeli Derince Training and Research Hospital, Istanbul, Turkey Erkan  Eski, MD  Department of Otorhinolaryngology, Başkent University, Izmir Hospital, İzmir, Turkey

Contributors

Contributors

xix

Görkem  Eskiizmir, MD, FTBORLHNS, PhD  Department of Otorhinolaryngology-Head and Neck Surgery, Manisa Celal Bayar University, Manisa, Turkey Christine  B.  Franzese, MD Department of Otolaryngology-Head and Neck Surgery, University of Missouri, Columbia, MO, USA Oren  Friedman, MD Otorhinolaryngology and Head and Neck Surgery Department, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Mustafa  Gerek, MD  Department of Otorhinolaryngology, University of Health Sciences, Gülhane Medical School, Ankara, Turkey Sercan  Göde, MD Department of Otorhinolaryngology, Medical Faculty, Ege University, İzmir, Turkey M.  Kürşat  Gökcan, MD Medical Faculty, Department of Otorhinolaryngology, Ankara University, Ankara, Turkey Joseph R. González, MD  Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA Ayse  Pelin  Gör  Yiğider, MD Department of Otorhinolaryngology, University of Health Sciences, Bakırköy Training and Research Hospital, Istanbul, Turkey Wolfgang  Gubish, MD Facial Plastic Surgery Department, Marien Hospital, Stutgart, Germany İsmail  Güler, MD Department of Otorhinolaryngology, Ankara Numune Training and Research Hospital, University of Health Sciences, Ankara, Turkey Murat Gümüşsoy, MD  Department of Otorhinolaryngology, University of Health Sciences, Tepecik Training and Research Hospital, İzmir, Turkey Emre Gunbey, MD  Adatip Hospital, ENT Clinic, Kurtköy, Istanbul, Turkey Pinar Gunbey, MD  University of Health Sciences, Kartal Lutfi Kırdar Training and Research Hospital, Department of Radiology, Istanbul, Turkey Ceren Günel, MD  Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Adnan Menderes University, Aydın, Turkey Kıvanç Günhan, MD  Department of Otorhinolaryngology, Medical Faculty, Manisa Celal Bayar University, Manisa, Turkey ENT Department, Medical Faculty, Celal Bayar University, Manisa, Turkey Selis  Gülseven  Güven, MD  Department of Otorhinolaryngology, Medical Faculty, Trakya University, Edirne, Turkey Işıl  Adadan  Güvenç, MD Department of Otorhinolaryngology, Çiğli Regional Training Hospital, İzmir, Turkey Deniz  Hancı, MD Department of Otorhinolaryngology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey Sheng-Po Hao, MD  Department of Otorhinolaryngology of Shin Kong Wu Ho-Su Memorial Hospital, New Taipei City, Taiwan Thomas  Hummel, MD Department of Otorhinolaryngology, Interdisciplinary Center for Smell and Taste, Dresden, Germany Fikret Ileri, MD  Department of Otorhinolaryngology, Memorial Hospital, Ankara, Turkey

xx

Mehmet İmamoğlu, MD  Medical Faculty, Department of Otorhinolaryngology, Karadeniz Technical University, Trabzon, Turkey Abdülkadir Imre, MD  Department of Otorhinolaryngology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, İzmir, Turkey Kagan Ipci, MD  Department of Otorhinolaryngology, Ankara Koru Hospital, Ankara, Turkey Jeffrey Janus, MD  Department of Otolaryngology, Mayo Clinic, Rochester, MN, USA Hong Ryul Jin, MD  Dr. Jin’s Premium Nose Clinic, Seoul, South Korea Martin Jurlina, MD  Medical Faculty, Otorhinolaryngology Department, Zagreb University, Zagreb, Croatia Livije  Kalogjera, MD Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Sestre Milosrdnice, Zagreb, Croatia Recep Karamert, MD  Medical Faculty, Department of Otorhinolaryngology, Gazi University, Ankara, Turkey Ayşe Karaoğullarından, MD  Department of Otorhinolaryngology, Adana Numune Training and Research Hospital, University of Health Sciences, Adana, Turkey Murat  Kar, MD Department of Otorhinolaryngology, Kumluca State Hospital, Antalya, Turkey Bülent Karcı, MD  Department of Otolaryngology, Medical Faculty, Ege University, İzmir, Turkey Sergei Karpischenko, MD  Department of Otorhinolaryngology, Pavlov First St. Petersburg State Medical University, Saint Petersburg, Russia Hideyuki  Kawauchi, MD Faculty of Medicine, Department of Otorhinolaryngology, Shimane University, Shimane, Japan Ercan  Kaya, MD Department of Otorhinolaryngology, Eskisehir Osmangazi University Medicine Faculty, Eskisehir, Turkey Fatma Tülin Kayhan, MD  Mega-Med Health Services Ltd Co, Istanbul, Turkey Department of Otorhinolaryngology, University of Health Sciences, Bakırköy Training and Research Hospital, Istanbul, Turkey Nesil Keleş, MD  Istanbul Faculty of Medicine, Department of Otorhinolaryngology, Istanbul University, Istanbul, Turkey David  W.  Kennedy, MD, FACS, FRCSI Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Tolga  Kırgezen, MD Department of Otolaryngology, Istanbul Training and Research Hospital, University of Health Sciences, Istanbul, Turkey Ayça Özbal Koç, MD  Florence Nightingale Hospital, Istanbul, Turkey Bülent Koç, MD  Bülent Koç Rhinoplasty Center, İstanbul, Turkey Elif Gülin Koçan, MD  Department of Otorhinolaryngology, Dr. Nafiz Körez State Hospital, Ankara, Turkey Gabriela  Kopacheva-Barsova, MD, PhD Faculty of Medicine, Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia

Contributors

Contributors

xxi

Hakan  Korkmaz, MD Department of Otorhinolaryngology, Medical Faculty, Yıldırım Beyazıt University, Ankara, Turkey Muhsin Koten, MD  Department of Otorhinolaryngology, Medical Faculty, Trakya University, Edirne, Turkey Gary  Kreps, PhD, FAAHB Department of Communication, Center for Health and Risk Communication, George Mason University, Fairfax, VA, USA Babur  Küçük, MD, PhD Medical Faculty, Department of Otorhinolaryngology, Ankara University, Ankara, Turkey Nagehan Erdoğmuş Küçükcan, MD  Department of Otorhinolaryngology, Çukurova State Hospital, Adana, Turkey Umut  Can  Kücüksezer, PhD Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey Tolgar  Lütfi  Kumral, MD Department of Otorhinolaryngology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey İhsan  Kuzucu, MD Department of Otorhinolaryngology, University of Health Sciences, Ankara Numune Training and Research Hospital, Ankara, Turkey Stephan Lang, MD  Department of Otorhinolaryngology-Head and Neck Surgery, University Hospital Essen, Essen, Germany Jivianne T. Lee, MD  Rhinology and Endoscopic Skull Base Surgery, Department of Head and Neck Surgery, University of California Los Angeles School of Medicine, Los Angeles, CA, USA Donald Leopold, MD  Division of Otorhinolaryngology, Department of Surgery, University of Vermont Medical Center, Burlington, VT, USA Andreas Lintermann, MD  Institute of Aerodynamics and Chair of Fluid Mechanics, RWTH Aachen University, Aachen, Germany Simulation Laboritory Highly Scalable Fluids and Solids Engineering, Jülich Aachen Research Alliance Center for Simulation and Data Science (JARA-CSD), RWTH Aachen University, Aachen, Germany Andrey Lopatin, MD  Medical Department, Policlinic No. 1, Business Administration of the President of Russian Federation, Moscow, Russia Jacques  Magnan, MD Department of Otolaryngology, Head and Neck Surgery, Hopital Nord, Marseille, France Abdelwahab Mahgoun, MD  ENT and Facial Plastic Surgery Center, Setif, Algeria Ali Reza Mesbahi, MD  Department of ENT & Facial Plastic Surgery, Khodadoust Hospital, Shiraz, Iran Raşit Midilli, MD  Lider Centrio Midilli ENT Clinic, İzmir, Turkey Department of Otorhinolaryngology, Medical Faculty, Ege University, İzmir, Turkey Mario Milkov, MD  Medical Faculty, Department of Otorhinolaryngology, Varna University, Varna, Bulgaria Eva  Kathryn  Miller, MD Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA Ranko Mladina, MD  ENT Department, Univ. Hospital Center Zagreb, Zagreb, Croatia

xxii

Jeffrey S. Moyer, MD  Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA Gheorghe  Mühlfay, MD Department of Otolaryngology, University of Medicine and Pharmacy of Targu Mureş, Targu Mureş, Romania Selçuk Mülazimoğlu, MD  Department of Otorhinolaryngology, Ankara University School of Medicine, Ankara, Turkey Joaquim  Mullol, MD, PhD Unitat de Rinologia & Clínica de l’Olfacte, Servei d’Otorinolaringologia, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain Immunoal·lèrgia Respiratòria Clínica i Experimental (IDIBAPS), CIBERES, Barcelona, Catalonia, Spain Nuray Bayar Muluk, MD  Department of Otorhinolaryngology, Medical Faculty, Kırıkkale University, Kırıkkale, Turkey Charles M. Myer III, MD  Department of Otolaryngology Head and Neck Surgery, Cincinnati Children’s Hospital and Medical Center, Cincinnati, OH, USA Robert M. Naclerio, MD  Department of Surgery, Section of Otolaryngology, University of Chicago, Chicago, IL, USA Hesham  Negm, MD Department of Otorhinolaryngology, Cairo University, Medical University, Cairo, Egypt Pamela Nguyen, MD  Department of Radiology, Medical Center, Columbia University, New York, NY, USA Joao Flavio Nogueira, MD  Department of Otorhinolaryngology, Universidade Estadual do Ceará, Fortaleza, Brazil Ramazan  Öçal, MD Department of Otorhinolaryngology, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey Fatih Oghan, MD  Medical Faculty, Department of ORL & HNS, Kutahya Saglik Bilimleri University, Kütahya, Turkey Oğuz Öğretmenoğlu, MD  ENT Specialist, Ankara, Turkey Tuğba Koçak, MD  Losante Children’s and Adult Hospital, ENT Clinic, Ankara, Turkey Metin  Onerci, MD Department of Otorhinolaryngology, Medical Faculty, Hacettepe University, Ankara, Turkey Nezih  Orhon, PhD Faculty of Communication Sciences, Anadolu University, Eskisehir, Turkey Amr Osama, MD  Radiology Department, Cairo University, Medical University, Cairo, Egypt Aslıhan  Semiz  Oysu, MD Department of Radiology, Ümraniye Training and Research Hospital, University of Health Sciences, Istanbul, Turkey Cagatay Oysu, MD  Medical Faculty, Department of Otolaryngology, Marmara University, Istanbul, Turkey Cevdet  Özdemir, MD Department of Pediatric Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Turkey Division of Pediatric Allergy and Immunology, Department of Pediatrics, Istanbul Faculty of MedicineIstanbul, Istanbul University, Istanbul, Turkey Erdoğan  Özgür, MD Medical Faculty, Department of Otorhinolaryngology, Muğla Sıtkı Koçman University, Muğla, Turkey

Contributors

Contributors

xxiii

Orhan  Özturan, MD Department of Otorhinolaryngology, Bezmiâlem Vakif University, Istanbul, Turkey Sedat  Ozturkcan, MD Izmir Katip Çelebi University, Ataturk Training and Research Hospital, İzmir, Turkey Berke Özücer, MD  ENT Department, Istanbul Hospital, Başkent University, Istanbul, Turkey Erkan Özüdoğru, MD  Department of Otorhinolaryngology, Eskisehir Osmangazi University Medicine Faculty, Eskişehir, Turkey Pietro Palma, MD  The Milan Face Clinic, Milan, Italy Department of ORL/HNS, University of Insubria, Varese, Italy James  Palmer, MD ENT Department, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Gaetano Paludetti, MD  Agostino Gemelli Hospital Foundation, Catholic University of the Sacred Heart, Head and Neck Surgery Area, Institute of Otorhinolaryngology, Rome, Italy Anthony Papavassiliou, MD  ORL Clinic at Athens Medical Center-Psihiko Hospital, Athens, Greece Desiderio  Passali, MD Medical Faculty, Department of Otorhinolaryngology—Head and Neck Surgery, University of Siena, Siena, Italy Giulio  Cesare  Passali, MD Department of Otolaryngology—Head and Neck Surgery, University of Sacro Cuore, Rome, Italy Norman  Pastorek, MD Department of Facial Plastic Surgery, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY, USA Ruby  Pawankar, MD, PhD, FRCP, FAAAAI Allergy Section, Department of Pediatrics, Nippon Medical School, Tokyo, Japan Ercan  Pinar, MD Department of Otorhinolaryngology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, İzmir, Turkey Mehmet  Özgür  Pınarbaşlı, MD Medical Faculty, Department of Otorhinolaryngology, Eskişehir Osmangazi University, Eskişehir, Turkey Emmanuel  P.  Prokopakis, MD, PhD Department of Otorhinolaryngology, University of Crete School of Medicine, Crete, Greece William Reisacher, MD  Otolaryngology Department, Weill Cornell Medical College, New York, NY, USA Chae-Seo  Rhee, MD, PhD Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, South Korea Philippe Rombaux, MD  Otorhinolaryngology Department, Saint-Luc University, Brussels, Belgium Michael  Rudenko, MD, PhD, FAAAAI The London Allergy and Immunology Centre, London, UK Ethem  Sahin, MD Department of Otorhinolaryngology, Bayindir Içerenköy Hospital, Istanbul, Turkey Özlem Naciye Şahin, MD  Department of Pediatrics, Acıbadem Mehmet Ali Aydınlar Medical Faculty, Istanbul, Turkey Cem Saka, MD  Department of Otorhinolaryngology, University of Health Sciences, Dıskapı Yıldırım Beyazit Training and Research Hospital, Ankara, Turkey

xxiv

Emine Güven Şakalar, MD  Department of Otorhinolaryngology, Yunus Emre State Hospital, Eskisehir, Turkey Engin Umut Sakarya, MD  Otorhinolaryngology Department, Sada Hospital, İzmir, Turkey Suela  Sallavaci, MD, MSc, PhD Department of ORL-HNS, University Hospital Centre “Mother Teresa”, Tirana, Albania Glenis  Scadding, MD, FRCP RNTNE Hospital, University College Hospitals London, London, UK Adin  Selçuk, MD Department of Otorhinolaryngology, University of Health Sciences, Kocaeli Derince Training and Research Hospital, Istanbul, Turkey Brent  Senior, MD Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Ela Araz Server, MD  Department of Otolaryngology, University of Health Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey Ola Omar Shahin, MD  Pediatric Psychiatry Department, Cairo University, Cairo, Egypt David  Sherris, MD Department of Otolaryngology-Head and Neck Surgery, Buffalo University, Buffalo, NY, USA Tania Sih, MD  Medical School at University of Sao Paulo, Sao Paulo, Brazil Neven Skitarelic, MD  Department of Health Studies, University of Zadar, Zadar, Croatia Faculty of Medicine, University of Rijeka, Rijeka, Croatia Murat Songu, MD  Ataturk Training and Research Hospital, Izmir Katip Celebi University, İzmir, Turkey Gordon Soo, MD  The ENTific Centre, Central, Hong Kong Michael  B.  Soyka, MD Department of Otorhinolaryngology Head and Neck Surgery, University Hospital and University of Zurich, Zurich, Switzerland Slobodan  Spremo, MD  Department for Otorhinolaryngology, University Clinic Center of Republic Srpska, Banja Luka, Bosnia and Herzegovina Milan Stankovic, MD  Clinic for Otorhinolaryngology, University Clinical Center Nis, Niš, Serbia D. Donald Stevenson, MD  Division of Allergy, Asthma and Immunology, Scripps Clinic, San Diego, CA, USA A. Volkan Sünter, MD  Department of Otorhinolaryngology, University of Health Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey Nihat  Susaman, MD  Department of Otorhinolaryngology, University of Health Sciences, Elazığ Training and Research Hospital, Elazıg, Turkey Ahmet Emre Süslü, MD  Department of Otorhinolaryngology, Medical Faculty, Hacettepe University, Ankara, Turkey Emel Tahir, MD  Department of Otorhinolaryngology, Ondokuz Mayıs University, Ankara, Turkey Emel Çadallı Tatar, MD  Department of Otolaryngology, Dışkapı Yıldırım Beyazıt Training and Research Hospital, University of Health Sciences, Ankara, Turkey Regan  Thomas, MD Department of Otolaryngology-Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Contributors

Contributors

xxv

Gökçe  Tanyeri  Toker, MD Department of Otorhinolaryngology, Haydarpaşa Numune Training and Research Hospital, University of Health Sciences, Istanbul, Turkey Department of Otolaryngology—Head and Neck Surgery, Izmir Katip Celebi University, Ataturk Training and Research Hospital, İzmir, Turkey Sema Zer Toros, MD  Department of Otorhinolaryngology, University of Health Sciences, Haydarpaşa Numune Training and Research Hospital, Istanbul, Turkey Mümtaz Taner Torun, MD  ENT Department, Bandırma State Hospital, Bandırma, Turkey Elina  Toskala, MD, PhD, MBA  Department of Otolaryngology-Head and Neck Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA Gilbert  J.  Nolst  Trenité, MD  International Federation of Facial Plastic Surgery Societies, Amsterdam, The Netherlands Harun  Üçüncü, MD Medical Faculty, Department of Otorhinolaryngology, Muğla Sıtkı Koçman University, Muğla, Turkey Seçkin  Ulusoy, MD Department of Otorhinolaryngology, Şişli Kolan Hospital, Istanbul, Turkey İstanbulEsthe Private Clinic, Istanbul, Turkey Halis Unlu, MD  Unlu Private Clinics, İzmir, Turkey Ahmet Ural, MD  Medical Faculty, Department of Otorhinolaryngology, Bolu Abant İzzet Baysal University, Bolu, Turkey Yavuz  Uyar, MD Department of Otorhinolaryngology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey Uzdan  Uz, MD  Department of Otorhinolaryngology, University of Health Sciences, Izmir Bozyaka Training and Research Hospital, İzmir, Turkey ENT Department, Bozyaka Training and Research Hospital, İzmir, Turkey Peter Tomazic Velentin, MD  Department of General Otorhinolaryngology, Head and Neck Surgery, Medical University of Graz, Graz, Austria Claudio  Vicini, MD  Department of Head-Neck Surgery, Otolaryngology, Morgagni Pierantoni Hospital, Head-Neck and Oral Surgery Unit, Forlì, Italy Stephan Vlaminck, MD  AZ St-Johns Hospital, Bruges, Belgium Klaus Vogt, MD, PhD  Faculty of Medicine, Centre of Experimental Surgery, University of Latvia, Riga, Latvia Douglas  C.  von Allmen, MD Department of Otolaryngology Head and Neck Surgery, University of Cincinnati, Cincinnati, OH, USA Becky  M.  Vonakis, MD Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA Alperen Vural, MD  Department of Otorhinolaryngology, Erciyes University, Kayseri, Turkey Andrew A. Winkler, MD  Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA Sarah  K.  Wise, MD Department of Otolaryngology-Head and Neck Surgery, Emory University School of Medicine, Atlanta, GA, USA Katharine Woessner, MD  Division of Allergy, Asthma and Immunology, Scripps Clinic, San Diego, CA, USA

xxvi

Husamettin Yasar, MD  Department of Otorhinolaryngology, University of Health Sciences, Haseki Training and Research Hospital, Istanbul, Turkey Demet  Yazıcı, MD Department of Otorhinolaryngology, University of Health Sciences, Adana Numune Training and Research Hospital, Adana, Turkey Ozgur  Yigit, MD Department of Otorhinolaryngology, University of Health Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey Asli Sahin-Yilmaz, MD  Department of Otorhinolaryngology, University of Health Sciences, Ümraniye Training and Research Hospital, Istanbul, Turkey Baki Yılmaz, MD  Private Practice, Caddebostan Mah. Cemil Topuzlu Cad. (Intermed Doktor Ofisleri Kat 3), Istanbul, Turkey Metin Yılmaz, MD  Faculty of Medicine, Otorhinolaryngology Department, Gazi University, Ankara, Turkey Mustafa  Deniz  Yılmaz, MD ENT Department, University of Health Sciences, Antalya Training and Research Hospital, Antalya, Turkey Ozge Yilmaz, MD  Department of Pediatric Allergy and Pulmonology, Medical Faculty, Celal Bayar University, Manisa, Turkey Arzu  Yorgancıoğlu, MD Department of Pulmonology, Medical Faculty, Celal Bayar University, Manisa, Turkey Erkan  Yüksel, PhD Faculty of Communication Sciences, Anadolu University, Eskisehir, Turkey Hasan  Yuksel, MD Department of Pediatric Allergy and Pulmonology, Medical Faculty, Celal Bayar University, Manisa, Turkey Dmitry Zabolotny, MD  Department of Otolaryngology, Academician of National Academy of Medical Sciences, Kiev, Ukraine Luo  Zhang, MD, PhD Beijing Institute of Otolaryngology, Beijing TongRen Hospital, Beijing, China Duygu  Zorlu, MD Department of Pulmonology, Medical Faculty, Ahi Evran University, Kırşehir, Turkey

Contributors

1

Introduction Ranko Mladina

1.1

 nce Upon a Time, There O Was a Nose…

Once upon a time, there was a Homo erectus with a humanoid head and two dark holes over his upper lip. One million years ago, or even more, the owner of the head had just slowly started to become bipedal, spending more and more time of the day in an erectile position. It was much easier and quicker to take a look around than to climb on tree branches to see what is going on in the vicinity and onwards. Still, there were two dark holes over the upper lip. These two holes were entrances to the nasal cavities. So, once upon a time, there was a nose.

1.2

 ome Anthropologic Considerations S Regarding Nasal Septal Deformities

According to anthropologic studies and archeological findings, nasal cavities in Homo erectus have been very large, in any case larger than they are in a modern man. This might suggest the importance of both breathing and respiratory roles of the nose once upon a time. Unfortunately, there are no data available on the deformities of the bony parts of the nasal septum which could have been usable and helpful for the study and reconstruction of the possible nasal septal deformities. What we know today is the fact that the erectile position of the Homo erectus caused the changes of at least three anthropometric parameters: the angulation of the skull base (Huxley’s angle), cranio-palatal angle, and pronounced prominence of the external nose. As to the skull base angulation, it does not exist in quadrupeds and their skull base is flat; whereas, in man, owing to the erectile position, there is an angulation between the anterior and posterior half. The posterior part of the base descends. The tip of the angle is located at the level of the pituitary gland. The angle is opened in the anterior and inferior direction, and in adult subjects it measures approximately 135°. It is generally believed that

the development of the sphenoid sinus has been closely connected to the angulation of the skull base since in animals this sinus has been never found. Interestingly, this angulation does also not exist in children. It starts to develop only during the early puberty. This confirms the old rule which says: the ontogenesis is just a short recapitulation of the phylogenesis. During the twentieth century, some authors advocated the theory that the development of some nasal septal deformities has been the result of the pressure from the so-called “cranial pincers” [1]. The anterior arm of these pincers is the anterior skull base while the other arm is the posterior skull base. According to this theory, all anatomical contents that are located within the radius of the pincers action could be squeezed and partially boosted in the anterior direction. Nasal septal skeleton is not a homogenous structure. On the contrary, it looks like a mosaic since there were nine pieces of bones and cartilages involved in this structure: intermaxillary bone, crista nasalis of the maxillary palatine process, crista nasalis of the horizontal lamina of the palatine bone, sphenoidal rostrum, crista nasalis of the frontal bone, crista nasalis of the nasal bones, cartilaginous quadrangular lamina, perpendicular plate of the ethmoid bone, and the vomer (Fig. 1.1). Such a heterogeneous structure presumably could be easily crumpled by adequate forces. Still, the hypothetic acting of the “pincers” implies only the acting of the posterior arm since the anterior one is supposed to be the entire time horizontal. In this case, the forces that squeeze the septum could act from behind and the only deformity that could be the result of this action is the development of type 3 (Fig. 1.2) according to Mladina classification of nasal septal deformities [2]. This means that the deflection of the septum in a vertical plane can happen, just at the weak point: at the borderline between the quadrangular (cartilaginous) lamina and the perpendicular plate of the ethmoid bone. Since type 3 septal deformity is not at all an expected finding in the children nose, in case this type can be clearly identified in child under the age of 12, one should consider the possibility of the presence of flat foots in particular child,

R. Mladina (*) ENT Department, Univ. Hospital Center Zagreb, Zagreb, Croatia © Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_1

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since type 3 indicates strong pressure from the posterior branch of the basocranial angle (clivus, in fact). If so, the diminution of the physiologic Huxley’s angle to the values lower than 135° could lead to the chain reaction of the changes of spine natural curvatures (arches), such as cervical lordosis, thoracic kyphosis, lumbar lordosis, sacral kyphosis and, finally, the changes of the foot arch, which could be elongated. Children of the age from 7 to 9 years who wear bigger number of shoes that vast majority of the equally height and aged colleagues do, probably have elongated foot arch and therefore longer foot. If we try to elaborate the length of the arch, we would need the formula like this one:

Fig. 1.1  The mosaic-like structure of the nasal septum: (1) intermaxillary bone; (2) crista nasalis of the maxillary palatal process; (3) crista nasalis of the horizontal lamina of the palatine bone; (4) sphenoidal rostrum; (5) crista nasalis of the frontal bone; (6) crista nasalis of the nasal bones; (7) quadrangular lamina; (8) perpendicular plate of the ethmoid bone; (9) vomer

Fig. 1.2  The anterior rhinoscopy view to the left-sided type 3. The great part of the middle turbinate is hidden by the deformity. The black dotted line indicates the usual borderline between the anterior, cartilaginous part of the septum and the posterior, bony one

But, this is not our field, it goes for mathematic and physics. To calculate the length of the sinew for the particular arch would perhaps be even more complicated because it requires very high level of mathematic operations. And, moreover, to know more about the elasticity and final resistance of the particular imagined sinews of the mentioned spinal arches is impossible without the “fractal analysis”, i.e., real mathematical experts. Because of that, to truly understand the mutual relationships between four or five substantive arches, directly linked to each other in a vertical line and the possible physical consequences on the lowest arch, is the matter to be considered by the engineers, not doctors. Still, it seems to be quite enough, so far, to know that the type 3 septal deformity in children younger than puberty age, with the negative data on trauma against the nose, the flat foots problem must be checked up since this malformation can be identified during the orthopedic examination in very many of the young children carrying type 3. Still, it is amazing what one can see during the anterior rhinoscopy or an endoscopic examination of the nose. This vertical deformity is not normally found in children [3], but in adults it is the most frequent type (20.4%)! [4]. In terms of that, since the angulation of the skull base reaches its maximum in adult age, it makes sense to believe that the development of type 3 nasal septal deformity has something to do with the acting of the “cranial pincers.” Later on, in the year 1990, it was Mladina who published for the first time the possible influence of some other factors to the development of nasal septal deformities. He studied on the possible influence of the angle defined by Scott [5] that is formed by two arms: one is defined by two points, i.e., the nasion (N) and the center of the sella turcica (S), and the second arm is defined by the anterior and posterior nasal spines (ANS and PNS) (Fig. 1.3). Some individuals have the cranio-palatal angle and consequently have the so-called occipitopetal skull shape (Fig. 1.4), while others do not show any angle between these two lines and have the so-called frontopetal skull shape [6, 7] (Fig. 1.3). The cranio-palatal angle is connected to the length of the caudal process of the quadrangular lamina of the nasal septum which

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N S

ANS PNS

Fig. 1.3  Schematic drawing representing a typical frontopetal skull shape. The line defined by the anterior nasal spine (ANS) and posterior nasal spine (PNS) is parallel to the line defined by nasion (N) and sella point (S)

N S

ANS PNS

Fig. 1.4  Schematic drawing representing a typical occipitopetal skull shape. The line defined by the anterior nasal spine (ANS) and posterior nasal spine (PNS) makes an anteriorly opened angle with the line defined by nasion (N) and sella point (S). Blue arrow indicates the caudal process of the quadrangular cartilaginous septal plate

is inserted between the superior edge of the vomer and inferior border of the perpendicular plate of the ethmoid bone. The greater the value of the cranio-palatal angle, the longer the caudal process. It seems that the angulation per se allows the progressive growth of the caudal process of the quadrangular, cartilaginous lamina of the nasal septum backwards in the space between the upper edge of the vomer and inferior edge of the perpendicular plate of the ethmoid bone (Fig. 1.4, blue arrow). In addition, this contributes essentially to the instability of this part of the septal “mosaic” structure enabling the deflection of the septum laterally. The lateral deflection is always more emphasized as deeper in the nose. The final result is type 5 septal deformity (Fig. 1.5). It was found that in cases with the existing cranio-palatal angle, the incidence of type 5 is higher than in subjects without it. Both the angulation of the skull base (Huxley’s angle) and cranio-palatal angle can be observed and measured on the lateral craniograms or on sagittal CT scans.

Fig. 1.5  Endoscopic view to the right-sided type 5 nasal septal deformity. It goes for the unilateral, ascending, almost basal crest (in literature, it is colloquially called “septal spur” or “septal crest”). The opposite side of the septum is in rule almost flat or slightly lumpy

1.3

External Nose During Millennia

One should not forget that great changes in the architecture of the human external nose have happened during the millennia. What we know today is the fact that, as a final result of the phylogenesis, there is an obvious, significant reduction of the splanchnocranium on account of the neurocranium (Fig. 1.6) [8]. Owing to the skull base angulation, all the anatomical structures located within the arms of the “cranial pincers,” for example, the so-called splanchnocranium, remain under the specific pressure exerted by the cranial pincers and are therefore extruded anteriorly. Hence, the “cranial pincers” are probably responsible for the development of the external nose prominence. Furthermore, “cranial pincers” are considered responsible for the fact that nasal septal deformities are found in humans, but not in quadrupeds! [9]. What we have today connected to the length of the caudal process is a type 5 nasal septal deformity (NSD) (Fig. 1.5), which usually has longer caudal process than other types of NSD.  This is a very well-known fact to all those who frequently perform septal surgery. Furthermore, this type has been clinically proven to be dominantly inherited from one generation to the other, which suggests that the existence of some chromosomal deletion is responsible for the onset of this deformity. The intensity and the side of this deformity obviously are not inherited, but the typical appearance is. In addition, the incidence of this type has been found to be very

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Fig. 1.6  The photo has been taken in the Museum of the Neanderthal Man in Krapina, Croatia. The author put his head within the frames of the hole behind the picture of the Neanderthal man’s skull. It is obvious that there is a difference in the height of the frontal region and a great difference in presumed dimensions of the piriform aperture: it seems to be much larger in Neanderthal man. The protrusion of the anterior part of maxilla as a characteristic of the Neanderthal man seems to be substantially reduced in Modern man

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Fig. 1.7  Coronal CT scan of the paranasal sinuses showing a typical appearance of type 5 NSD. The left septal mucosa is a little lumpy

Fig. 1.8  Type 6 nasal septal deformity. Left-sided deep groove (yellow arrow), right-sided basal septal crest (green arrow). The floor of the right nasal cavity cannot be seen because of a substantially lower position in comparison to the left side

high in patients who survived an acute coronary syndrome (ACS) and afterwards showed a positive finding of the coronary angiography! Hypothetically, this suggests a possible connection between the certain chromosomal deletion responsible for the onset of type 5 and the certain degree of predisposition to the coronary diseases [10, 11]. Type 5 can

be easily recognized on the coronal CT scans of the paranasal sinuses (Fig. 1.7). There is another type of nasal septal deformities which has been proven as congenital, directly and dominantly inherited from one generation to the other, like it was shown for type 5. This is type 6 (Fig. 1.8). This type is characterized

1 Introduction

Fig. 1.9  The skull of the Homo erectus. The left nasal floor is higher than the right one (dotted line and white arrows). The remnants of the perpendicular plate of the ethmoid bone can be also identified (yellow arrow)

Fig. 1.10  The piriform aperture of the Neanderthal man. Note the asymmetry between the floors of the nasal cavities (dotted yellow line). The left one is lower. The intermaxillary bone is sloped to the left (white arrow)

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by an asymmetrical level at the bottom of the nasal cavities; typical basal, horizontal, and anteriorly positioned groove of the nasal septum on the side of the higher nasal floor; and a basal septal crest at the same depth of the nasal cavity on the opposite side, i.e., on the side of the lower nasal floor. The fact that the asymmetry between the positions of nasal floors can be seen in skulls of a Homo erectus and a Neanderthal man suggests that type 6 is really very, very old and possibly existed even at that time (Figs. 1.9 and 1.10). What we know today is that in very many cases of type 6 NSD, the uvula duplex can be seen during the careful oropharyngoscopy. Type 6 NSD can be also easily recognized on the coronal CT scans of the paranasal sinuses (Fig. 1.11). It usually remains overlooked because of the lack of knowledge. Radiologists usually mention this deformity simply as a “septal deviation” or “deviated septum,” with no details which indicates that even they are not familiar with the classification of nasal septal deformities having been published long time ago, i.e., in the year 1987. In addition, as it was in case of type 5, type 6 has been found in an extremely high incidence in ACS patients with a positive coronary angiography finding as well [3, 10, 11]. Contrary to that, these two types are not very frequent within the general ENT population or in some specific ENT subgroups like the chronic sinusitis [12, 13].

Fig. 1.11  Coronal CT scan of the paranasal sinuses of an adult patient showing the typical appearance of type 6 NSD. Please note the submucosal cleft: the palatal processes of the left and right maxilla have not been connected during the growth of the skull (yellow arrow). In the middle of the gap that exists between them, there is the intermaxillary bone (red arrow) resembling a letter “Y,” but with obviously asymmetrical wings. The floor of the right nasal cavity is positioned lower (blue, dashed line) than the left one as it is the level of the hard palate (asymmetry!). Because of that, the asymmetry of the hard palate can be seen during oropharyngoscopy. The palpation of the hard palate along the raphe palati (the midline) with the tip of the forefinger is recommended in such cases, because in many of them, a submucosal, hidden cleft can be palpated! Uvula bifida can be found also in very many of the patients carrying type 6

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One issue has to be clarified hereby: septal deformity per se, being it type 5 or type 6, is not responsible for the onset of an ACS with positive coronary angiography finding. Neither type 5 nor type 6 can seriously disturb the bilateral nasal breathing and thus influence the cardiac function as it has been suggested in the literature for a long time. The focus in case of type 5 or type 6 NSD should be put on the genesis of these two deformities and their genetic roots and possible belonging to the same genetic code responsible also for some cardiac diseases! Therefore, septal surgery per se will never prevent the onset of the ACS! Once it is there, it is too late! But it would not be too late in the sense of preventing future ACS attacks, because once one of these two types is found in a certain person, it will automatically mean that this person carries some chromosomal change (deletion?) responsible for the cardiac disease and thus will be able to work on the prevention, be it in a classical way as it is valid in nowadays medicine or, hopefully in a near future, much radically, i.e., to undergo chromosomal engineering process to eliminate this gene aberration and to be protected at least from the onset of the ACS with positive coronal angiography like it fortunately happened in case of beta thalassemia. The Chinese molecular biologist succeeded to “knockout” the “bad guy,” i.e., the chromosomal

aberration responsible for the onset of thalassemia. They performed their intervention in the embryo of the young couple, who are both suffering thalassemia. The baby was born healthy! [14].

Fig. 1.12  Type 7 nasal septal deformity (Passali deformity). The right-­ sided type 2 completely obstructs the entrance to the right nasal cavity. Left nasal cavity has been explored by the 0° endoscope. The yellow dotted line represents the posterior fracture line of the quadrangular, cartilaginous septal plate, i.e., the line where quadrangular plate has its conjunction to the perpendicular, bony ethmoidal plate (lamina perpendicularis). Note the white arrow that indicates type 3 on the left septal

side which, together with type 2 on the right septal side green arrow, forms, in this very case, the so-called Z-shaped septal deformity. Official name for such deformity is type 4. In addition, there is also a deep type 5 septal deformity (green arrow). This is only one of the possible options of the combinations among various types of septal deformities

1.4

Septal Deviation or Septal Deformity?

The term “septal deviation” is widely accepted and has been used colloquially for a very long time. But, sincerely speaking, it means nothing to the modern rhinologist. Why? Because from an etymologic point of view, it is a kind of deflection from the middle line or from some other given path and nothing more (from Latin: de via, meaning a kind of deflection or misalignment from the expected, normal path). Such a term, once entered into the patient’s records, would instantly lose its meaning even for the same physician after a week or two when the patient comes for a control examination, because the physician will not be able to remember what exactly he or she has found in the patient’s nose during the first examination. Moreover, it means nothing particularly to any other physician the patient brings his medical records to. “Septal deviation” is a general term with no specific meaning. It says nothing

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about the real appearance of the particular septum! The use of the term “septal deformity” (from Latin: de forma, meaning the change of the shape) is etymologically much more appropriate. On the other hand, if the deformity is assigned and named properly according to some wellknown and widely accepted classification, it will help any physician reviewing the patient’s records in the future to know exactly what the septum looked like at the time of the first examination. It will be a precious document to every rhinologist who uses the same classification system and “speaks” this particular type of language, the so-called “Rhinology Esperanto.” To be fluent in “Rhinology Esperanto” means to know the classification. Knowing it, one should be able to automatically conceive the appearance of the particular type of the septal deformity. For instance, Mladina classification is simple to memorize. It is composed of the so-called four vertical deformities (from anterior to posterior) and two horizontal ones. This order has been proposed in the year 1986 by the late colleague Irfan Ljubijankić, a resident from Bosnia at ENT Dept. of the Clinical Hospital Center in Zagreb, Croatia. His idea made this classification more user-­friendly and easy to memorize. There is also the seventh type (the socalled “Passali deformity”) which is, in fact, a variable combination of the previous types. This type is also called “crumpled septum” because of the variety of possible changes in its shape (Fig. 1.12).

1.5

 linical Implications of the Nasal C Septal Deformities

According to the most recent publications, for example, “International Consensus Statement on Allergy and Rhinology: Rhinosinusitis,” published as a supplement of the International Forum of Allergy and Rhinology (IFAR) [15, 16], this type as well as type 3 (“C”- or “reverse C”-shaped septum) plays the most important role in the development of chronic rhinosinusitis! The pathophysiologic explanation for this fact is quite simple: type 3 substantially changes the value of the ipsilateral cross-sectional area. One nasal cavity is narrow because of the septal lateral convexity itself, whereas the other cavity is broad owing to the septal concavity. Both narrowness and breadth are not physiological for the inspired airstream. In the narrow side, the airstream meets the obstacle, the real strait between the septal convexity and the medial surface of the middle turbinate. To pass through the strait, the airstream has to elevate its speed. After passing through the strait, the airstream founds itself suddenly again in the large area behind the deformity. This produces whirling of the airstream. The high speed in the strait simply erases normal respiratory epithelium. The same effect produces also the turbulences that happen behind it. The result is a squamous metaplasia of the ostiomeatal complex (OMC) (Figs.  1.13, 1.14, and 1.15) [17].

Fig. 1.13  An axial CT scan showing the right-sided type 3 nasal septal deformity. The compensatory hypertrophy of the left middle turbinate (yellow arrow) and even its pneumatization suggest that the deformity is not a recent one, and neither has been produced by any kind of trauma against the nose. Most probably it has to do with the long-lasting developmental issue, i.e., by the forces coming from the “cranial pincers.” In this very case, the airstream will have the problem to get to the Cottle’s area 4 both on the right and left sides since there are obvious bilateral strives in the Cottle’s area 3

This leads directly to the impaired drainage system of the paranasal sinuses and gives the opportunity for the development of the chronic rhinosinusitis. The other side which is large, however, has the same consequences because of the effect of turbulences. This means that in case of type 3 deformity, both nasal cavities are jeopardized!

1.6

 he Nose and Forensic Medicine T Considerations

Knowing the types of nasal septal deformities could be very helpful also in the domain of forensic medicine since types 5 and 6 have been clinically proved to be inherited. That means none of them have anything to do with the trauma against the nose. In case a rhinologist, who is able to recognize at the very first sight type 5 or 6, is asked to the court as an expert

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Fig. 1.14  The histopathology image of the epithelium of the right middle turbinate. The mucociliary epithelium is simply erased and replaced by the simple, squamous cell epithelium (small white arrow). At the most prominent part of the turbinate, the squamous cell metaplasia is really very thin (big white arrow)

witness to give the opinion on the possible consequences of the trauma to the client’s nose, he or she will be able to categorically state that the certain trauma against the nose did not produce any of those types since they are inherited, and it can be easily proved in every single case (examination of the nose of the closest relatives of the family!). Contrary to types 5 and 6 which have been proven to be dominantly inherited and type 3 which we understand as a consequence of “cranial pincers” acting, types 1 and 2 have a different background. They are as in rule the consequence of the trauma against the nose. There is a term used to describe the cartilage bending in such cases: “greenstick fracture,” meaning that, like in case of greenstick in nature, a real fracture of the quadrangular plate is almost impossible. It can be only more or less seriously bended like it is the case with the greensticks. Still, the term “septal frac-

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Fig. 1.15  The identical region of the left middle turbinate as in Fig. 1.13. The metaplastic squamous cell epithelium here has several layers

tures” has been firmly accepted and used among rhinologists for years and decades, in spite of the fact that it is purely used for dogmatic apprehension. That is to say, it should be known that even in cases of obvious anterior vertical crooks of the nasal septum (types 1 and 2), no obvious “fracture” of the cartilage or any tissue gap was ever found, be it during the meticulous septal surgery or during the histological analysis. Regarding histology, the only issue that can normally be found in the region of the crook is local proliferation of the chondrocytes in the “heart” of the deflection (Figs. 1.16 and 1.17). The real disruption of the septal cartilage can be seen exceptionally as a result of serious nasal trauma. In these cases, the tissue discontinuity, i.e., the gap between two or more parts of the cartilage, can be identified. Besides, in cases of serious trauma against the nose, the distortions of the pyramid can also be seen (Figs. 1.18 and 1.19).

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Fig. 1.16 Histology of the septal cartilage (horizontal section!) through the right-sided vertical crook (type 2 septal deformity) of an adult patient. Despite an emphasized angulation, there are no signs of the discontinuity of the cartilage

Fig. 1.18  The consequence of the serious trauma against the nose. The force came from the patient’s left side and the cartilaginous part of the septum has been crushed. An emphasized type 2 septal deformity to the right side remained as a persistent consequence (red line). The bony pyramid was not involved in the trauma (dotted black line) and therefore is straight

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Fig. 1.17  A close-up view of the angulation shows a typical appearance of the so-called “greenstick fracture”: no tissue discontinuity (no gap), and the high amount of chondrocytes can be clearly seen, invading the damaged place

 eneral Conclusions Regarding Nasal G Septum

The use of classification when documenting nasal septal deformities gives us hope for future breakthroughs in the field of medicine. The physicians who speak “Rhinology Esperanto” will be (or already are?) able to think in advance about the clinical importance of the particular types of septal deformities as to act in sense of prevention of the onset of certain possible clinical conditions, knowing about their direct connection with the precisely defined types of nasal septal deformities. For instance, in the near future, it is expected that it is possible to lay the foundations for predicting someone’s predilection to acute coronary syndrome (ACS), as it has been spoken in case of types 5 and 6 (forming the National Register for

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Fig. 1.19  The appearance of the nasal pyramid after the serious trauma against the nose which came from the patient’s right side. The nasal bones have been fractured. The consequence was an emphasized type 4 septal deformity consisting of type 3 on the left side and type 2 on the patient’s right side. The whole pyramid has the inverse “C” appearance: rhinoscoliosis

types 5 and 6) as the modern basis for the future preventive regular examinations (lipids, body weight, cholesterol levels, etc.) or, as a next step, maybe even to help to avoid this possibility by means of the most recent molecular biology techniques [3, 11, 14]. To prevent forever the genesis of the cleft lip/palate in future newborns could be also hypothetically possible once molecular biologists will come closer to the chromosomal deletion, so cold 22q11.2 deletion, nowadays known as responsible for the onset of cardiac anatomical disorders that almost regularly come along with the cleft lip/palate pathology. It might go to the same deletion and molecular biologist might be able to eliminate this “bad guy” from the baby’s chromosomes during the embryonal stage, and no baby will be ever born in the close future with the cleft lip/palate syndrome! [16–18].

Olfaction

Going back to the Homo erectus, we can only presume that the nose in these creatures, once upon a time, was important not only regarding the nasal breathing but also because of the olfactory function. To have a good olfaction at that time was critical for the surveillance. What we have today is the particularly designed olfactory groove which consists of the horizontally positioned cribriform plate at the bottom, medially there is the bony crest (crista galli), and laterally there is the lateral plate. Through the numerous holes in the cribriform plate, the olfactory nerve fibers pass and connect the olfactory epithelium located at the roof of the nasal cavity and the olfactory region of the brain. What we know today is that the height of the lateral plate in this groove varies, and because of that Keros was the first to make a classification of the depth of the olfactory groove in three degrees (A, 1–3 mm; B, 4–7 mm; and C, 8–16 mm) [19]. The most frequent type is type B. It could be found in more than 73% of the population. The second most frequent is type A (in more than 25% of the population), whereas type C, which means an extremely deep olfactory groove, can be seen very rarely. What we have today from this very region is a clinical entity which in very many cases remains overlooked: pneumatized crista galli. It was found on the coronal and axial CT scans of the paranasal sinuses that the frequency of pneumatized crista galli varies from 2.4 to 37.5% [20–27]. However, the most recent researches performed directly on the human skulls, not on the patients and their CT scans, showed preliminary results strongly suggesting much higher frequency of the pneumatized crista galli, i.e., 66.6%! Because of that and of the possibility that this aerated space within the bone belonging to the anterior skull base is in fact a part of the paranasal sinuses community, the modern rhinologist should pay particular attention to it, especially because the radiologists extremely rarely describe this phenomena in their findings and recordings. The rhinologist should be capable to independently interpret the patient’s CT scans of the paranasal sinuses. The overlooked sinusitis within the pneumatized crista galli still can be the focus for the permanent subfebrility, general weakness, and stubborn headaches (Fig.  1.20). The possible sinusitis within the pneumatized crista galli should be taken into consideration in cases of hyposmia or even gradually developed anosmia! Anyhow, this pathology belongs to an experienced and well-equipped (navigational system) endoscopic sinus surgeon, not at all to the neurosurgeon.

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Still, what we have today, which seems to be connected to the vomeronasal organ remnants from the certain subject’s fetal age [28–33] (remember the famous saying that the onto genesis is just a short recapitulation of the phylogenesis), is the phenomenon of the isolated airspace, aerated cavity within the perpendicular plate of the ethmoid bone, which we simply call sinus septi nasi (SSN). This entity can be found in more than 34% of the human skulls. The width of the SSN formations varies from 0.5 to 4.2 mm, the length varies from 3.5 to 18.8 mm, and the height varies from 3.8 to 17.7 mm (Fig.  1.21). From a clinical point of view, sinus septi nasi could be diseased as any other paranasal sinus (even though much, much less frequently) and acts as a focus for long-lasting fevers or subfebrilities, headache, and general weakness. It also can provoke the Vasomotor Rhinitis! The modern clinicians should be aware of this entity, particularly because of the fact that sinus septi nasi is also, as it is the case with sinus cristae galli, almost never described in radiological findings and records. One should not forget that this cavity exists in more than one-third of the adult population!

Fig. 1.20  A coronal CT scan showing typical Keros B type of olfactory slope depth (up to 7 mm). Crista galli is somewhat irregularly shaped owing to the irregularity of the anterior skull base (right half of the skull base is lower than the left one). The cavity within crista seems to be fulfilled with the contents identical to those in the ethmoid cells. The radiological coefficient suggested a mucosal edema. An emphasized pneumatization of both middle turbinates is also visible

1.9

Pheromones and Sinus Septi Nasi

In addition, the nose in ancient, prehistoric times served most probably also as a reliable receiver of the information on pheromones that possibly could have been emitted by the members of the community. For these purposes, the so-called vomeronasal organ was there. It was located bilaterally within the separate, parallel bony canals extending along the superior border of the vomer, slightly ascending towards the prechoanal region and ending up in the relatively large bony reservoir within the posterior half of the perpendicular plate of the ethmoid bone. What we have nowadays are the remnants of the vomeronasal organ only: the anatomical relicts in some, rare individuals could be emphasized and are easy to follow by means of histology, whereas in a vast majority of modern people, the vomeronasal organ seems to be lost forever.

Fig. 1.21  A very large cavity within the nasal septum is nicely visible. It is fulfilled with certain contents and located very posterior, thus suggesting the possible derivation from the sphenoid sinus itself. But, if you take a look more carefully, you will find out that the CT cut has been performed at the level of the posterior third of the middle turbinate. This fact excludes the possibility that this cavity within the nasal septum belongs to the sphenoid sinus. Furthermore, the anterior wall of the sphenoid sinus always stays in the same line with the posterior wall of the maxillary sinuses, and here it is obvious that the image has been taken more anterior to the posterior wall of the maxillary sinus

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1.10 The Lateral Nasal Wall Once upon a time, a lot of active volcanoes existed all over the world. Homo erectus knew very well that it is better to stay away from them. But, from time to time, there was a volcano problem right in the middle of their head. In fact, it was the situation when an empyema of the maxillary sinus had developed. The pain, high fever, and weakness could have been fatal at that time. The only chance for the diseased individual was unloading of the content collected and captured within the diseased maxillary sinus. At that time this chance was literally the only one: disruption of the membrane over the fontanel(s) on the lateral nasal wall. Those who experienced the eruption of the maxillary sinus volcano have been saved. This was the only way to survive an acute purulent maxillary sinusitis. The hole in the disrupted fontanel remained for the rest of the individual’s life since it never cicatrizes. What we have today is, of course, completely a different story. We have nasal smears, microbiology, antibiotics, and peroral and local decongestants. One should not forget to insist on bacteriological smears, both for aerobes and anaerobes. Anaerobes are, as in rule, forgotten which sometimes results in fiasco of the treatment. Besides, when taking a bacteriological smear which will be stored or immediately transported to the bacteriological lab, it should be emphasized that the smear should have to be put into the beaker containing Stuart’s agents. Both aerobic and anaerobic bacteria can stay alive on a room temperature with these conditions up to 72 h. This is a very practice in case when the smear has been taken on Friday late afternoon and the laboratory has been already closed until the Monday morning. Particular attention should be paid to the maxillary sinus puncture procedure since this maneuver belongs to the history and should not be practiced any longer. Why? First, the puncture means the disruption of the bony medial wall of the maxillary sinus under the inferior turbinate. The hole in this place never cicatrizes. Second, during the irrigation, the pressure within the sinus rises to the extreme values since the natural ostium has been already blocked by the inflammation. The only way out for the growing amount of the liquid coming into the sinus under enormous pressure (from the syringe) is the weakest point, i.e., the thin membrane covering the natural bony defect at the lateral nasal wall, the so-­ called nasal fontanel. The membrane disappears during the “eruption” and the purulent secretion could be irrigated out from the diseased sinus, but the hole in the fontanel never heals and never cicatrizes as well! So, what we have today is the fact that people who suffer from the postnasal drip are unaware of the fact that their lateral nasal wall perhaps has a hole in the fontanel or even in the inferior nasal meatus.

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From the pathophysiological point of view, here goes for the so-­called Two Holes Syndrome [34, 35]. In other words, once it has been recovered from the empyema, maxillary sinus continues with the normal function, which means the mucociliary transport system of its respiratory mucosa works normally and expels the mucus out through the natural ostium. But, on its physiologic way towards the nasopharynx, the mucus falls into the trap: the hole in the fontanel region! It finds itself again in the maxillary sinus. Since the maxillary sinus mucosa does not recognize the artificial opening and simply overrides it during the mucociliary action, the normal mucus continues to come out into the nasal cavity time and again, thus forming the so-called recirculation mucous ring, for the first time described by Kane [36]. This morphologic problem can be diagnosed only by means of nasal endoscopy, preferably a flexible one, i.e., by means of fiberendoscopy of the nose in  local, superficial anesthesia. The typical finding looks as in Figs.  1.22 and 1.23. The only effective way to eliminate this symptom is to perform a short endonasal endoscopic procedure which consists of the removal of the tissue bridge between the natural maxillary sinus ostium and the hole in the fontanel, thus forming the only one opening, the so-called middle ­antrostomy. Once the two holes become one hole, the postnasal drip immediately stops.

Fig. 1.22  An endoscopic view of the left ostiomeatal complex. The defect of the fontanel is large (yellow arrow). The green arrow indicates the uncinate process, whereas the white one shows the lateral surface of the middle turbinate

1 Introduction

Fig. 1.23  An endoscopic view to the left nasal cavity. Black arrow indicates the inferior border of the middle turbinate. The mucopurulent discharge flows towards choana and proceeds down to the throat: postnasal drip

1.11 Epistaxis or Nosebleeds Vascular diseases are a major threat to human health nowadays. Hypertension, cardiovascular disease, varicose vein disease of the lower legs, and bleeding hemorrhoids are now increasingly recognized as inflammatory diseases. The role of inflammation cytokines in the pathogenesis of these diseases is very important. The lamina propria in the nasal mucosa is rich in blood vessels and humoral mediators. Epistaxis, whether spontaneous or otherwise, is experienced by up to 60% of men population in their lifetime, with 6% requiring medical attention [37]. The etiology of nosebleeds can be divided into local and general causes; however, most of them (80–90%) are actually of unknown etiology [38]. One of the most frequent forms of nosebleeds is the anterior one, i.e., coming from the Kiesselbach’s (or Little’s) vascular network. It is characterized with the inclination to recur from time to time. Mladina was the first to highlight this phenomenon describing it as a group of factors that act simultaneously at the same place, i.e., within the nasal vestibule, and named this pathological entity as REKAS.  REKAS is an abbreviation of Recurrent Epistaxis from Kiesselbach’s Area Syndrome. He published REKAS first in [39].

13

It has been found that 90% of patients suffering from REKAS simultaneously suffered from hemorrhoids and/or dilatations of the lower leg veins. Clinical observations suggest a possible mutual pathophysiologic relationship between Kiesselbach’s and anorectal venous plexus. This relationship is also suggested in the reverse direction: significantly more than two-thirds of primarily hemorrhoidal patients (83.01%) showed simultaneous vascular dilatations within their Kiesselbach’s plexuses, but none of these patients have ever had recurrent nosebleeds. There is one more thing they did not have (contrary to REKAS group): the anterior septal deformity [40]. Furthermore, REKAS and hemorrhoidal disease, despite being different clinical entities, frequently appear in the primarily REKAS patients or their closest relatives (more than 90% out of all!). At the same time, all of the REKAS patients did have a certain degree of the anterior septal deformity, which primarily hemorrhoidal patients did not have at all. Therefore it is generally believed that Kiesselbach’s vascular plexus belongs to the same group with the anorectal and lower leg venous plexuses (others of this group are brain and esophageal venous network). We also presume that the anterior septal deformity is a crucial factor for the predisposition to the onset of the inflammation of the nasal vestibule skin (vestibulitis nasi), while vestibulitis nasi is the trigger for the onset of typical recurrent nosebleeds from the Kiesselbach’s plexus. The factor which is absolutely unavoidable when REKAS is concerned is heredity! The hereditary caused predisposition to the pathological, everlasting dilatations of the veins in typical venous plexuses in the human body (brain, Kiesselbach’s, esophagus, anorectal, and crural region) is crucial. Whenever the doctor recognizes typical enlargements of the veins in the Kiesselbach’s plexus, he or she should keep in mind that the patient will answer positively to the questions on possible hemorrhoidal disease or varices cruris disease, strokes, etc. in the patient’s closest relatives. The modern treatment of recurrent nosebleeds from Kiesselbach’s area is based on the well-known fact that the inflammation of the nasal vestibule skin is always the trigger for the bleeding. The signs of inflammation of the nasal vestibule are always found in REKAS patients, and the most frequent pathologic microorganism isolated usually is Staphylococcus aureus. Because of that, an adequate treatment should consist of antibacterial drug first. In case the patient does not bleed at the time of the examination and the typical clinical picture and the history data speak in favor of REKAS, the doctor should try the conservative treatment which consists of two components: the antibacterial peroral treatment by means of the drug effective against Staphylococcus aureus, i.e., trimethoprim-sulfamethoxazole (2 × 2 tbl. during 5 days and 2 × 1 tbl. during the next 5 days), and the local treatment by means of combined medical cream composed of steroid and gentamycin (again one of the most effective antistaphylococcal drugs) for the vestibular skin inflammation.

14

In case we are dealing with an acute anterior nosebleed episode, we can stop the bleeding by simply pressuring the ala over the bleeding area for some 10 min. Care should be taken to gradually and slowly diminish the force of pressure by the end of the procedure. The abrupt abortion of pressure could produce the detachment of the freshly developed clot, and the bleeding simply continues; in case the bleeding does not stop or does not entirely stop, cauterization of the bleeding vessel(s) should be performed. The cauterization should never be bilateral in the corresponding area since this could result in the defect of the most anterior part of the nasal septum! Cauterization could be performed be it by means of chemical agents (silver nitrate of 5, 10, or 20% solution), softly applied by the cotton swabs over the dilated vessels, or by means of bipolar coagulation. Particular types of lasers can also be applied. During the intervention, it is more than useful to give the patient an ice cube or a very cold beverage to keep it as long as possible in a close contact with the hard palate. The vasoconstriction of the hard palate mucosa vessels will produce simultaneous vasoconstriction also in the Kiesselbach’s area, helping in this way to stop the bleeding. Since anterior nasal septal deformities like type 1 or 2 (Figs. 1.12, 1.24, 1.25, and 1.29b) or type 6 (Fig. 1.8) have been found in a very high incidence of REKAS patients and in hemorrhoidal patients suffering at the same time with intermittent nosebleeds from Kiesselbach’s plexus, septal surgery should be seriously considered, but still as a last option. It is generally believed that anterior septal deformi-

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ties can produce longitudinal distensions of the particular veins in the Kiesselbach’s plexus producing micro-breaches of the vascular wall and thus enabling lower resistance against disruption and consequent bleeding. Once we are speaking on most anterior, vertical septal deformities, i.e., about type 1 or type 2, a few words on the possible clinical implications of these two types should be mentioned. Type 1 means a mild unilateral vertical ridge in a valve area, which slightly interferes with the function of the nasal valve; thus, in most cases, this has a mild clinical importance. Clinically, some people, for reasons which are not quite clear, tolerate this type better than others. The exception could appear when this type is connected to subluxation or even luxation of the columellar septal edge. The subluxation or luxation could bother patients both in aesthetic and functional sense, but type 1 septal deformity is, in most of the cases, irrelevant in terms of the patient’s subjective valuation of nasal breathing quality. Exceptionally, it can act as a predilecting factor for the impaired nasal breathing in patients with unusually high columella and thin, flagging alar cartilages. In these cases, the entrance to the nose is already narrower than the usual one since a high columella enables a certain degree of nasal alae stretching. Additionally, in cases when they are thin and lax, they will collapse during deep nasal inspiration. The result will be the nestling of both alae to the anterior septum, which will be much stronger on the side of the deformity (Fig. 1.26).

S

Fig. 1.24  The left ala is nestling to the nasal septum during the forced nasal inspiration

Fig. 1.25  Endoscopic view of the region behind the left-sided type 2 nasal septal deformity. S: very posterior part of the nasal septum; white arrow indicates the strawberry-like hypertrophy of the inferior turbinate tail, blocking entirely left choana

1 Introduction

15

nal nuclei in the medulla oblongata are the nuclei of the cervical plexus. Here begins the efferent arm of the nasopulmonary reflex. The next point in this arm is the phrenic nerve which is located within the cervical plexus. The phrenic nerve, furthermore, is responsible for the innervation of the diaphragm muscles (efferent arm of the nasopulmonary reflex). Because the phrenic nerve cannot be adequately agitated in such circumstances, no adequate contraction of the diaphragm happens on the related thoracic side. Furthermore, a lesser contraction of the diaphragm also results in more superficial pulmonary breathing on this side. One more thing should be taken into account here: septal deformity itself disables a direct contact between the airstream and nasal fontanel receptors, thus impeding normal regulation of the tracheobronchial and vagal tone. The naso-­pulmonary reflex is distorted or totally blocked. Therefore, the most important clinical features connected to type 2 septal deformity are impaired nasal and pulmonary breathing. One should not forget the usual endoscopic finding of the most posterior parts of the nasal cavity in type 2: a strawberry-­like hypertrophy of the mucosa of the inferior turbinate tail (Fig. 1.27).

Fig. 1.26  Left-sided type 1 nasal septal deformity. Yellow line surrounds the most emphasized part of the Kiesselbach’s plexus

Type 2 means unilateral vertical ridge, which is much more emphasized than in type 1, i.e., it stays in close contact with the limen nasi. This is region of the anterior nasal valve, supposed to form an angle with the septum of 15°, and in case of type 2, this angle is seriously compromised, i.e., substantially diminished. Besides, from the physical point of view, it remarkably narrows or even totally blocks the air passage through the related nasal side. From the clinical point of view, the shape of this deformity produces a typical situation: the branches and the cogs of the nasociliary and nasopalatine nerves (belonging to V1 and V2 branches of the trigeminal nerve), which have a dense network in the nasal cavity, do not have appropriate contact with the airstream during the inspiration. In fact, they cannot be adequately agitated by the airstream. Because of that, the beginning of the afferent arm of the so-called naso-­pulmonary reflex that connects the nose and the diaphragm is blocked and, consequently, the nuclei of the trigeminal nerve in the medulla oblongata, where the afferent arm stops, cannot be reached and agitated. Furthermore, the closest “neighbors” to the trigemi-

Fig. 1.27  Left-sided type 2 nasal septal deformity. The dilated, delicate vessels belonging to Kiesselbach’s plexus are clearly visible

16

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Even more, there are data in the literature that suggest the strong influence of type 2, combined with the consequently hypertrophic mucosa of the tail of the inferior turbinate, to the middle ear pressure [41]. In conclusion it can be stated that in cases where types 1 and 2, particularly type 2, are assessed as potential factor for the patient’s nasal troubles, septal surgery should be seriously considered as a good option. The CT scan is also very typical for this deformity (Fig. 1.28). Up to this point, almost all types of nasal septal deformities have been mentioned, described, and discussed in terms of their clinical influence. Two types have not been described well so far: type 4 and type 7 (Passali deformity). Both of these two types are in fact a combination of already known types. For instance, type 4 is a simple combination of two “vertical” deformities, i.e., type 1 or 2 and type 3. The latter usually stays on the opposite side than type 1 or 2, thus forming a typical “S”- or “Z”-shaped septum (Figs. 1.29 and 1.30).

L

Fig. 1.28  Type 2 presented at axial CT scans. The grayish part of the nasal septum, which means the cartilaginous part of its skeleton, is seriously deflected to the patient’s left side as seen in Fig. 1.2, thus obstructing the passage of the airstream through the left nose

Type 7, however, is colloquially called “crumpled septum” since it may contain a combination of both “vertical” deformities (types 1, 2, 3, or even 4) and at least one of the “horizontal” ones (types 5 and 6). This type of deformity has been recognized as the most common septal deformity among the chronic rhinosinusitis patients [15, 16].

1.12 C  obweb Rhinitis or Rhinitis Arachnoidalis Modern rhinologists should take into consideration the existence of the so-called cobweb rhinitis or rhinitis arachnoidalis [42], particularly when dealing with the patients with the chief complaint of showing an unusual clinical picture presented as subjective feeling of a unilateral fullness in the facial projection of the maxillary sinus and ipsilateral nasal obstruction. Such patients frequently have a subjective feeling that they cannot take a deep breath in general, like their lungs have been stretched in a way. Surprisingly, both anterior rhinoscopy and fiberendoscopy, before and after the decongestion of nasal mucosa, show no remarkable morphologic finding in terms of any particular edema of the nasal mucosa, septal deformity, or nasal polyposis. Anterior ­rhinomanometry and acoustic rhinometry findings are within normal ranges also. CT scans of the paranasal sinuses show normal appearance. Still, there could be found unusual clinical findings in the nose of all these patients: transparent, very delicate mucous filaments that extend between the medial and lateral surfaces of the related nasal cavity, very much resembling a cobweb (Figs. 1.29a, 1.31, and 1.32). In 84% of patients presenting the clinical picture of the nasal cavity like this one, the molds of Fusarium (Fig. 1.33) and Paecilomyces species (Fig.  1.34) have been isolated, but only after 4 weeks of incubation on the usual Petri dish! The macroscopic aspect of the mold colonies isolated from the cobweb rhinitis patients is presented in Fig. 1.35 On the other hand, bacteria in rule are not found in bacteriological samples, even after 72 h of incubation, and because of that, the finding is automatically considered normal, which is obviously wrong. What is the pathophysiology of the nasal molds? The most important fact is that both Paecilomyces and Fusarium produce the so-called mycotoxins. Paecilomyces produce paecylotoxins, while Fusarium species produce fumonisins and trichothecenes. All of them have the same effect onto the nasal mucosa: an anesthetic one! They simply inhibit production and release of electric action potentials at the cogs of the nasopalatine and nasociliary nerve branches resulting in real local anesthesia. This is why some of the cobweb rhinitis

1 Introduction Fig. 1.29  A: the anterior rhinoscopy of the right nasal cavity. Type 3 obstructs the view to the head of the middle turbinate. Note the delicate, whitish filaments distended between the nasal septum and the middle turbinate (yellow arrow) suggesting the presence of the so-called “cobweb rhinitis” or rhinitis arachnoidea. It goes for the specific intranasal molds. This is the subject of the next section of this text. B: extremely emphasized left-sided type 2 which completely obstructs the entrance to the left nasal cavity

17

a

b

Fig. 1.31  Left nasal cavity. Type 1 septal deformity covers partially the anterior pole of the inferior turbinate, but the most remarkable details in this image are whitish delicate filaments distended between lateral and medial walls of this cavity. This is the typical clinical finding of the cobweb rhinitis Fig. 1.30  An axial CT scan clearly showing Z-shaped nasal septum, i.e., there is the left-sided type 2 and the right-sided type 3

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18

S

Fig. 1.32  View into the right nasal cavity of the patient suffering from nasal polyposis. A lot of delicate white filaments, particularly between the polypous mass and nasal septum, can be clearly seen. The polyp seems to be a solitary one and protrudes out of the ostiomeatal complex. The nasal septum shows typical finding for type 6 septal deformity with a relatively deep groove (white arrow) and the prominence of the so-­ called basal crest (black arrow), which is, in fact, the right ala of the intermaxillary bone. S: septum

Fig. 1.34  The microscopic view to the Paecilomyces species colonies grown on the Sabouraud agar 2% (BBL Becton Dickinson and Company, New York, USA)

Fig. 1.35  The macroscopic aspect of the colonies of intranasal molds having grown on the Petri dish. The colonies of Paecilomyces usually show a dark area in the central part of the colony (yellow arrows), while Fusarium species resemble snowflakes

Fig. 1.33  The microscopic view to the Fusarium species colonies grown on the Sabouraud agar 2% (BBL Becton Dickinson and Company, New York, USA)

patients, in spite of relatively unobtrusive morphologic finding regarding the nasal septum and lateral nasal wall morphology, still complain of the impaired nasal breathing! Caution: at the very first sight, it seems to be more than clear that this is just a subjective feeling. But because of the local anesthetic effect, the nasal mucosa is not capable to “feel” the airstream passing through the nasal cavities, regardless

1 Introduction

that in some cases the morphology of both nasal cavities is more than normal. Because of that, in cobweb rhinitis patients, it is not exclusively the subjective feeling. The naso-thoracal reflex is again compromised like in type 2 septal deformities! The result can be the distorted pattern of pulmonary breathing, the so-called “diaphragm supported.” In such cases, the Respifit test results confirm that the diaphragm is not at all involved in the breathing process of the particular patient! Besides, these mycotoxins can suppress humoral and cellular immunity and cause tissue breakdown [43]. The same goes for the feeling of nasal obstruction in patients suffering from atrophic rhinitis (ozena), in whom the anesthetic effect remains even after the removal of all crusts that are usually found in their nasal cavities. The branches and cogs of the trigeminal nerve together with the subepithelial mucosal layers have been destructed by Klebsiella ozaenae! Fortunately, the treatment of the cobweb rhinitis is very simple: the hypertonic seawater solutions have to be puffed (intranasal sprays) into the respective nasal cavity several times a day for at least 7 up to 10 days. It goes for a simple washing out of the molds. No particular medications, be it peroral or systemic, are needed at all. The patient’s symptoms and the cobweb-like formations simply disappear.

1.13 Final Remarks I believe this introduction chapter will serve both experienced colleagues dealing with the nose in their everyday practice and those who are at the very beginning of their career. Once upon a time, there was a nose. Yes, that’s true. But, the nose survived all enormously huge amounts of millennia throughout the human history and is still here with us. Our duty is to be humble in front of it since we are far from completely understanding this structure. The nose deserves our full attention because human health, in so many aspects, seems to be closely connected to it. So, in general, the nose is the center of our life or we could accentuate: IT’S ALL ABOUT THE NOSE! This sentence is not far from the message hidden within the main title of this amazing book: ALL AROUND THE NOSE!

References 1. Mladina R. The role of maxillary morphology in the development of pathological septal deformities. Rhinology. 1987;25:199–205. 2. Šubarić M, Mladina R. Nasal septum deformities in children and adolescents: a cross sectional study of children from Zagreb, Croatia. Int J Ped Otolaryngol. 2002;63(1):41–8.

19 3. Mladina R, Čujić E, Šubarić M, Vuković K. Nasal septal deformities in ear, nose and throat patients: an international study. Am J Otolaryngol. 2008;29:75–82. 4. Scott JH. Dentofacial development and growth. London: Pergamon Press; 1967. p. 179. 5. Mladina R.  The influence of palato-cranial base (basomaxillary) angle on the length of the caudal process of the nasal septum in man. Rhinology. 1990;28:185–9. 6. Mladina R, Krajina Z. The influence of the caudal process on the formation of septal deformities. Rhinology. 1989;27:113–9. 7. Mladina R, Skitarelić N, Vuković K.  Why do humans have such a prominent nose? The final result of phylogenesis: a significant reduction of the splanchnocranium on account of the neurocranium. Med Hypotheses. 2009;73:280–3. 8. Mladina R, Skitarelić N, Skitarelić N. The human external nose and its evolutionary role in the prevention of obstructive sleep apnea. Letter to the editor. Otolaryngol Head Neck Surg. 2010;143:712–4. 9. Mladina R, Skitarelić N. Could we prevent unilateral cleft lip/palate in the future? Medical Hyptheses. 2009;73:601–3. 10. Mladina R, Skitarelić N, Raguž M, Carić T.  Type 5 and 6 nasal septal deformities: could we predict and prevent acute coronary syndrome attacks in the future? Med Hypotheses. 2015;85:640–4. 11. Carić T, Mladina R, Cingi C, Skitarelić N, Raguž M, Bergovec M, Starčević B, Šubarić M, Muluk NB.  Could nasal septal deformities type 5 and 6 be a predictive factor of the individual genetic predilection for the onset of an acute coronary syndrome? B-ENT. 2016;12:227–33. 12. Poje G, Zinreich JS, Skitarelić N, Đurić Vuković K, Passali GC, Passali D, Mladina R.  Nasal septal deformities in chronic rhinosinusitis patients: clinical and radiological aspects. Acta Otorhinolaryngol Ital. 2014;34:117–22. 13. Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, et  al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015;6(5):363–72. https://doi.org/10.1007/ s13238-015-0153-5. 14. Orlandi RR, Kingdom TT, Hwang PH.  International consensus statement on allergy and rhinology: rhinosinusitis. Int Forum Allergy Rhinol. 2016;6(S1):S3–S21. 15. Skitarelić N, Mladina R. Do nasal septal deformities have anything to do with chronic rhinosinusitis? International Forum of Allergy & Rhinology. 2016;6:1101. https://doi.org/10.1002/alr.21822. 16. Verwoerd CDA, Mladina R, Nolst Trenite GJ, Pigott RW.  The nose in children with unilateral cleft lip and palate. Int J Ped ORL. 1995;32:45–52. 17. Mladina R, Ostojić D, Koželj V, Heinzel B, Lj B.  Pathological septal deformities in cleft palate children. L'Otorinolaryngologia Pediatrica. 1997;(2–3):75–80. 18. Mladina R, Skitarelić N, Vuković K, Subarić M, Carić T, Orihovac Z.  Unilateral cleft lip/palate children: the incidence of type 6 septal deformities in their parents. J Craniomaxillofac Surg. 2008;36:335–40. 19. Keros P.  On the practical value of differences in the level of the lamina cribrosa of the ethmoid. Z Laryngol Rhinol Otol. 1962;41:809–13. 20. Basic N, Basic V, Jukic T, et al. Computed tomographic imaging to determine the frequency of anatomical variations in pneumatization of the ethmoid bone. Eur Arch Otorhinolaryngol 1999; 265: 269–271. 21. Som PM, Park EE, Naidich TP, Lawson V.  Crista galli pneumatization is an extension of the adjacent frontal sinuses. Am J Neuroradiol. 2009;30:31–3. 22. Socher JA, Santos PG, Correa VC, de Barros e Silva IC. Endoscopic surgery in the treatment of crista galli pneumatization evolving with localized frontal headaches. Int Arch Otorhinolaryngol. 2013;17(3):246–50.

20 23. Kim JJ, Cho JH, Choi JW, Lim HW, Somng YJ, Choi SJ, Yeo NK. Morphologic analysis of crista galli using computed tomography. J Rhinol. 2012;19(2):91–5. 24. Al Quadah MS. Anatomical variations in sino-nasal region: a computer tomography (CT) study. J Med J. 2010;44(3):290–7. 25. Poje G, Mladina R, Skitarelic N, Marjanovic Kavanagh M. Some radiological and clinical aspects of the sinus cristae galli. Romanian J Rhinol. 2014;13(4):31–6. 26. Manea C, Mladina R. Crista galli sinusitis- a radiological impression or a real clinical entity. Romanian J Rhinol. 2016;6(23): 167–17. 27. Hajiioannou J, Owens D, Whittet HB.  Evaluation of anatomical variation of the crista galli using computed tomography. Clin Anat. 2010 May;23(4):370–3. https://doi.org/10.1002/ca.20957. 28. Witt M, Wozniak W.  Structure and function of the vomeronasal organ. In: Hummel T, Welge-Lüssen A, editors. Taste and smell. An update. Adv Otorhinolaryngol, vol. 63. Basel: Karger; 2006. p. 70–83. https://doi.org/10.1159/000093751. 29. Stoyanov G, Moneva K, Sapundzhiev N, Tonchev AB. The vomeronasal organ - incidence in a Bulgarian population. J Laryngol Otol. 2016;130:344–7. 30. Estes RD. The role of the vomeronasal organ in mammalian reproduction. Mammalia. 1972;36:315–41. 31. Kratzing J. The structure of the vomeronasal organ in the sheep. J Anat. 1971;108:247–60. 32. Won J, Mair EA, Bolger WE, Conran RM. The vomeronasal organ: an objective anatomic analysis of its prevalence. Ear Nose Throat J. 2000;79:600–5.

R. Mladina 33. Trotier D, Eloit C, Wassef M, Talmain G, Bensimon JL, Doving KB, et al. The vomeronasal cavity in adult humans. Chem Senses. 2000;25:369–80. 34. Mladina R, Vuković K, Poje G.  The two holes syndrome. Am J Rhinol Allergy. 2009;23:602–4. 35. Mladina R, Skitarelić N, Casale M.  Two holes syndrome (THS) is present in more than half of the postnasal drip patients. Acta Otolaryngol. 2010;130(11):1274–7. 36. Kane KJ. Recirculation of mucus as a cause of persistent sinusitis. Am J Rhinol. 1997;11:361361–9. 37. Petruson B, Rudin R. The frequency of epistaxis in a male population sample. Rhinology. 1975;13:129–33. 38. Pope LER, Hobbs CGL. Epistaxis: an update on current management. Postgraduate Med. 2005;81:309–14. 39. Mladina R.  REKAS (recurrent epistaxis from Kiesselbach’s area syndrome). Chir Maxillofac Plast. 1985;15:91–5. 40. Mladina R, Čavčić J, Šubarić M.  Recurrent epistaxis from Kiesselbach's area syndrome in patients suffering from hemorrhoids: fact or fiction. Arch Med Res. 2002;33:1–2. 41. Salaheldin AH.  Effect of deviated nasal septum and hypertrophy of inferior turbinate on middle ear pressure. Pan Arab J Rhinol. 2012;2:59–65. 42. Mladina R, Skitarelić N. Cobweb rhinitis-rhinitis arachnoidea. We do have to keep an eye on this ! Romanian J Rhinol. 2011;3:109–11. 43. Nelson PE, Dignani MC, Anaissie E.  Taxonomy, biology, and clinical aspects of Fusarium species. Clin Microbiol Rev. 1994;7:479–504.

Part I Basic Science of Nose and Paranasal Sinuses

2

History of Rhinology Cemal Cingi, Metin Onerci, and Donald Leopold

2.1

Introduction

Rhinology refers to the study of the nose, paranasal sinuses, and nasopharynx. The field today involves an understanding of basic science principles including physiology as it relates to the mucociliary blanket, molecular biology with respect to the inflammatory process, and microbiology as it concerns the ever-changing spectrum of organisms that may infect the sinus passages. Equally important are the newer surgical procedures that deal with the disease in this anatomic region. The transition from open techniques to an endoscopic approach has enabled the modern physician to access vital structures in a more anatomic and functional manner [1]. During the second half of the nineteenth century, major progress was made in learning the anatomy and physiology of the nose and sinuses. With the beginning of the twentieth century, an outburst of technology aroused that provided notable advances in the kind and quantity of surgeries carried out. Nevertheless, the procedures of the nose and sinuses contain a remarkable potential of enhancing health or seriously damaging individuals. Within the middle of the twentieth century, the general scientific understanding appeared to have caught up with the care being provided, but as the century comes to an end, we are faced with another trend of surgical practice. Possibly, in hardly any other surgical field, one can experience this much of an imbalance between the biology and surgery. Probably, the upcoming century will see an improvement regarding the balance between these measures [2]. C. Cingi (*) Eskişehir Osmangazi University, Medical Faculty, Department of Otorhinolaryngology, Eskisehir, Turkey

Until the end of the Middle Ages, from time to time, obscure features were attributed to the sinuses, like holding the “grease” for the motion of the eyeballs, or enabling the brain to “drain its bad spirits” to the external world, bringing about names like “la cloaca del cerebro” by Sansovino in the sixteenth century. The old French expression of “rhume de cerveau” demonstrates these ideas having passed on into modern man’s vocabulary. During the seventeenth and eighteenth century, discussion was mainly about the function or purpose of the sinuses, and the rare anatomical studies were meant to support or prove one or the other’s “philosophies” [3]. Today’s knowledge of the anatomy to a great deal goes back to the basic work of Emil Zuckerkandl of Austria who, starting from the 1870s, described in subtle studies the anatomical and developmental details of the nose and sinuses, opening an entire new era regarding the clinical and surgical approach to the area. The several years around the turn of the century stand out with research on sectional and surgical anatomy, generating the specialty of rhinology and creating today’s principles of diagnosis and therapy of disorders of the nose and sinuses. Names such as Grünwald, Onodi, Hajek, and many more are closely associated with this particular productive interval [3]. Radiology, especially the progress of conventional and computed tomography through the last 40 years, assisted to “rediscover” the actual exciting details and complicated connections of the paranasal sinus system. Simultaneously, the development of the operating microscope and endoscope aided to create innovative ways for functional approaches and less radical microsurgery [3]. Historical progress of rhinology is also interesting. In this chapter, the history of rhinology is presented in detail.

M. Onerci Department of Otorhinolaryngology, Medical Faculty, Hacettepe University, Ankara, Turkey

2.2

D. Leopold Division of Otorhinolaryngology, Department of Surgery, University of Vermont Medical Center, Burlington, VT, USA e-mail: [email protected]

Ancient reports regarding the nose, paranasal sinuses, and olfactory functions and the efforts to handle diseases of this region are found from the earliest periods [4]. Egyptian med-

Ancient History

© Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_2

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icals were the pioneers of nasal surgeons. They utilized instruments to take away the brain through the nasal passages, as a stage of the mummification procedure [3, 5]. The earliest document of a nose examination in medical literature extends as early as the sixth century before Jesus, in the Hindu record “Sushruta Samhita” where they mention a tubular-shaped nasal speculum, prepared from bamboo tree, to remove tonsils and nasal polyps [5]. The ancient Egyptian papyri clearly document the embalming process by which practitioners would extract the brain through a transnasal portal of entry [6]. Not only did this practice indicate the sophistication of the mummification process but it also gave insight into the anatomic expertise of the ancient Egyptians. To our knowledge, the earliest named physician was the Egyptian Sekhet’enanch, who lived in approximately 350 BC. He was the attendant of Sahura, one of the pharaohs of the fifth dynasty. His legacy is engraved within the tomb of the king where it was discovered that “he healed the king’s nostrils”. Many other civilizations make reference to rhinology in their writings [7, 8]. The Bible and the Talmud contain numerous references to a variety of ear, nose, and throat diseases. The nose is recognized as the organ for breathing as quoted in Genesis (II) [9], when the “Lord God formed man of the dust of the ground and breathed into his nostrils the breath of life”. Furthermore, it is mentioned in the Babylonian Talmud that “a polyp shows itself by a bad smell of the nose”. Although diagnoses are inferred in these scriptures, treatments for the conditions are not mentioned. The classic Hindu document known as the Sanskrit Atharva Veda contained numerous bits of medical information including the diseases of the head and neck region. These writings documented the achievements of Hindu surgery. They described the manufacture of new noses by local flaps from the cheek or forehead. It is noteworthy that nasal amputation was the usual punishment for adultery during the time of that culture. It may therefore be implied that the Hindus were the originators of the modern rhinoplasty. Much of Chinese medicine was based on treatment by acupuncture including many nasal conditions [1].

2.2.1 Hippocrates, Celsus, and Galen 2.2.1.1 Hippocrates Hippocrates was born on the island of Cos in 460 BC and founded a medical school based on the belief that illness had a physical and rational explanation. History considers him the “father of medicine”. In many respects, he could also be considered the “father of rhinology”. In terms of rhinologic practice, he clearly documented the treatment of nasal fractures, insisting on the necessity of fracture reduction within the first 24 to 36 h after injury. He described the lifting of fragments of bone into place and described the use of inter-

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nal splints of “Carthaginian leather” to keep the fragments in place. For severely displaced fracture, he talked about tying a long leather thong around the head and fastening it to the temples by the use of glue [10]. His methods for removing nasal polyps were quite revolutionary, and the technique was practised by rhinologists into the first millennium, as written in Voltolini’s textbook in 1888 [9]. Hippocrates indeed defined management strategies to handle nose injuries. The injuries were categorized as contusions in soft tissues to complex bone injuries, suggesting specific procedures for every scenario, as the usage of bandages and braces with olive tree or reconstructions of nasal bone and cartilage. Hippocrates’s texts demonstrated the concern for nose traumas, as they were frequent incidents during those times, within both the military and athletes in tournaments in the ancient Greece. These kinds of procedures were customized and determined the management strategies up till the Middle Ages [3, 5]. To remove polyps, Hippocrates wrote about tying several strings to a sponge with the other end being fastened to a malleable probe that was pushed through the nasal passage into the nasopharynx. This sponge was then dragged across the nasal chamber and, if successful, brought the polyps with it. He described another technique for the more fibrotic polyps using the principle of the snare. He also described the use of hot irons for cauterization and advised a local application of a caustic powder to further control haemorrhage and prevent adhesions. It is most fascinating that his rhinologic practice in principle is similar to many of the techniques that are currently in practice. The next notable personality was Aulus Cornelius Celsus, a Roman nobleman who lived in the first century CE.  He wrote an extensive series of eight books of medical encyclopaedia, De Medicina, which was eventually discovered in the papal library in 1478 [11].

2.2.1.2 Celcus Celsus described the nose as “the two nasal passages separated by an intermediate bone. These passages break up into two branches, one for respiration and one leading to the brain through which we get our sense of smell”. Celsus is most noted for his description of the cardinal signs of inflammation, rubour, tumour, calour, and dolour. He also described nasal polyps, likening them in appearance to “the nipples of a female breast”. He treated polyps by using caustics and also by an operation. He described the use of a spatula-­ shaped instrument to mobilize the polyp from its stock and finally remove it with a type of hook. He talked about lung infections as possibly originating from the catarrh of the nasal passages [1]. 2.2.1.3 Galen Claudius Galenus, known as Galen, was born in Asia Minor (Bergama - Turkey now) in 131 AD [12]. His works [13]

2  History of Rhinology

offered a great advance in the knowledge of the anatomy of the upper respiratory tract based on precise anatomic dissection of animals. He recognized the nose as the beginning of the respiratory tract and described the muscles of the external nose as the dilators of the nostril. Galen categorized the conditions of the nose into two, namely, ozaenae and polyps. He believed that the sinuses contained fluid and mucus, which was produced by the brain and the pituitary gland and was subsequently released into the nose. Thus, he considered nasal catarrh as “a purging of the brain” [1, 12].

2.3

The Middle Ages

During this period, there was a concerted effort by rhinologists to gain a better understanding of the nasal chambers and how they functioned. This was accomplished by meticulous anatomic dissections and astute clinical observations. Nevertheless, some myths prevailed from ancient times [1].

2.3.1 Fifteenth and Sixteenth Centuries Even though Hippocrates had indeed defined parts of the anatomy of the nose, the nasal components were actually identified in the 1500s. In 1489, Leonardo da Vinci drew the nasal turbinates as well as the nasal sinuses. Nevertheless, these paintings were truly discovered in Milan, in 1901. In 1536, George Thomas firstly noted the posterior insertions of the middle turbinate in his report “Anatomiae pars prior” [3, 5, 13]. The very first book which solely focused on the surgery methods for rhinoplasty was released in 1597 as “Treaty on Rhinoplasty”. The author, Gaspare Tagliacozzi, was a professor at the University of Bologna and an expert in this topic. He defined new methods for rotating flaps over the nasal pyramid [3, 5, 13]. In 1651, Highmore, in England, identified the maxillary sinus, and for quite some time this sinus was referred to as the Highmore’s antrum [13]. Moreover, in the Middle Ages, strange functions were ascribed to the paranasal sinuses, like keeping oils to lubricate the eyeball movements, or a drainage room for malignant spirits within the brain. The paranasal sinuses were named after such functions, for instance, “la cloaca del cerebro”, as reported by the Spanish physician Sansovino, in the 1600s [13]. The anatomy physicians of that time included Andreas Vesalius (1514–1564), who released his remarkable paper in De Humani Corporis Fabrica in 1543 [14]. He described the maxillary, frontal, and sphenoidal sinuses, declaring that they contained nothing but air. He also named the posterior choanae.

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Other anatomists of the day were Bartolomeus Eustachius (1520–1574) and Gabriel Fallopius (1523–1562), who succeeded Vesalius at Padua. It is noted that Fallopius, whose name is associated with a number of body parts, was also a significant physician in rhinology. He created a wire snare for taking out nasal polyps. He writes: “I take a silver tube which is neither too broad nor too narrow, and then a brass or steel wire, sufficiently thick, preferably the iron wire from which harpsichords are made. This doubled I place in the tube, so that from this wire a loop is made at one end of the tube by which, used in the nares, I remove the polypi” [15]. Another Latin physician, Petras Forestus (1522–1597), claimed to cure ozaenae by “copious nasal douching with perfumed white wine in which cypress, roses, and myrrh were dissolved”. He also used silver nitrate and alum rubbed up with honey and applied with a probe [16]. On the other hand, Fabricius treated ozaenae with “an iron cannula inserted in the nostril, so long that it will reach the end and equal the length of the ulceration and occupy the cavity of the nostrils. Through this, a glowing hot instrument is to be introduced which, however, should not reach beyond the cannula”. It is possible that the ulcerations that Fabricius referred to as ozaenae were probably manifestations of syphilis [8]. Through the Middle Ages, nasal catarrh continued to be thought of as a “purging of the brain”, with mucus percolating through the bony foramina in the region of what we now call the cribriform plate. The noted Thomas Willis (1621– 1675), whose name is associated with the circle, believed that nervous fluids were secreted by the brain and were then carried to different parts of the body by the nerves. He thought that these serous humours were being secreted into the nose through tubular structure within the mucosa [17]. A German physician, Conrad Victor Schneider (1614– 1680), published a classic treatise on membranes of the nose entitled De Catarrhis in 1660 [18]. He established that the origin of the nasal secretions could not be from the cranial cavity but in fact emanated from the nasal mucous membranes themselves. This was an important revelation.

2.3.2 Seventeenth and Eighteenth Centuries Throughout the seventeen and eighteen centuries, the main medical debate regarding the nasal area was the function and purpose of paranasal sinuses. Numerous conditions were linked to these areas such as halitosis and acne, and the ­suggested procedure was a total or partial middle turbinate resection. In England, Drake and Cowper mentioned several patients with halitosis resulting from the suppuration of maxillary sinus in 1707. The case was treated by taking the teeth out, thus reaching the maxillary sinus through the alveolus [13]. In 1765, Jourdain in France made an attempt to

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treat suppurations of maxillary sinuses by irrigation through the natural ostium in the middle meatus, but this was not really effective. Although Lamorier started draining the maxillary sinus through the oral cavity in 1743, he did not publish his work before 1768. However, his technique of draining the maxillary sinus through the tooth socket continued to be the conventional method for quite long [13, 19].

2.3.3 Nineteenth Century Henle, who was working in Berlin in 1841, was able to distinguish several types of epithelium and, in particular, wrote about the functions of the lining of the nose and respiratory organs, which was an epithelium-bearing cilia [13]. In 1886, whilst in Vienna, Mikulicz-Radecki described first how the maxillary sinus could be approached through the inferior meatus, and this was followed up in 1893 by Caldwell, who invented a technique for approaching the maxillary sinus via the canine fossa by excising mucosa and creating an opening laterally within the inferior meatal wall. Boenninghaus pioneered Caldwell’s method amongst European surgeons in Berlin in 1896, adding value to it by creating a fold of mucosa that would overlie the entrance to the sinus. The Frenchman, Luc, working in Paris, did not know Caldwell’s discovery when, in 1897, he created a surgical approach identical to that of the American, Caldwell. Our current knowledge of the structural anatomy of this body area in large part hinges on the work of the Austrian, Emil Zuckerkandl, whose 1870 discussions of nasal and paranasal sinusal anatomy delineated the anatomical components, paving the way for a novel clinical area and added to surgical knowledge. The decades leading up to the year 1900 saw advances in surgical and sectional anatomical research by such men as Grunwald, Hajek and Onodi. Their work has enabled the beginnings of rhinology as a distinct discipline and laid the foundations of contemporary practice in the identification and treatment of nasal and sinus pathology [13]. The invention of endoscopy by Philipp Bozzini in 1806 gave impetus to rhinological diagnostic and operative technique. It was Czermak, however, who coined the word “rhinoscopy” and disseminated the usage of the nasal speculum followed by the nasal endoscope in 1879 [3, 5, 13, 19]. Many books have been published for the purpose of medical education in the Ottoman period. Some books in the ENT field had participated in this development. The first book for the diagnosis and treatment of nasal disease, after the preparation by the “Hekimbaşızade” (Chief Physician, Dr. Muhiddin in 1897), was reviewed by publication commission of “Mekteb-i Tıbbıye-i Şahane” (medical school). It was published in 1901 in “Mahmud Bey” printing (Istanbul)

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with the consent of “Maarif Nezareti” (Ministry of Education) (consent date: December 8, 1897; consent number: 572) [20].

2.3.4 Twentieth Century There was an ongoing enthusiasm amongst surgeons for rhinology at the start of the twentieth century, which, coupled with the progress in anaesthetics, led to the development of new operations aimed at ameliorating nasal and paranasal sinusal diseases. Hirschmann was able to inspect the maxillary sinus by means of an endoscope adapted for the purpose in 1901. Ermiro Estevam de Lima from Brazil became famous all over the surgical world through his accessing the ethmoidal sinus and sphenoidal sinus by a transmaxillary route, soon to be denoted internationally as the “Ermiro de Lima” procedure, and he also invented the curette which was named in his honour. The same man set up the Brazilian Society of Rhinology in 1974, Roberto Machado Neves Pinto and Sérgio de Paula Santos being counted amongst the founding fathers of the society. Harvey Cushing initiated those neurosurgical procedures progressing via the sphenoid in 1912 [21]. Lynch detailed his sinusal surgery on the frontal and ethmoid in 1921, working in New Orleans [20]. Around this time, in 1926, John Logie Baird, who also developed a system for television, received a patent for the transfer of images through glass fibre-optic cable, an invention which led Harold Hopkins to create his scopes in 1948. Basil Hirschowitz and Karl Storz [3, 13, 19] performed gastrointestinal endoscopy by means of the non-rigid fibre-­ optic cable then available. The history of surgery to the nasal septum began when Killian and Freer undertook total septectomy and submucosal resection in the early 1900s, followed by Cottle who performed septoplasties in the mid-century. Septal submucosal resection was outlined by Killian in 1904 and Freer the following year. In 1897, Lothrop wrote that the inferior meatus closed quickly following antrostomy, whilst Freer spoke out against radical surgery, maintaining that the maxillary sinus needed to remain open to the air. In the first decade of the 1900s, Killian and Siebenmann proposed that an infected maxillary sinus could be drained via uncinectomy of the middle meatus [22]. Most of the early surgical procedures lacked efficacy due to the incomplete knowledge of the physiology of the nasosinal region that existed at this time. Jacques Joseph defined thoroughly reduction rhinoplasty for the nasal dorsum along with particular deformities. He especially brought up the social and psychological elements to be considered before rhinoplasty. Additionally, he developed a number of tools, which are still being used presently. He reported on surgical correction of the nose in excellent

2  History of Rhinology

detail and founded intranasal rhinoplasty in Europe on a methodical base at the turn of the twentieth century. Also, he wrote a detailed book on rhinoplasty in 1928. Simultaneously, John Roe in New  York continued to carry out corrective instead of reconstructive surgery and popularized intracartilaginous technique for the bulbous tip [22]. In contrast to anticipations, the 1930s to 1950s resulted in slowing in rhinology. This situation was because of antibiotics, which significantly diminished the requirement for surgical treatment of the paranasal sinuses. Furthermore, laryngology and otology progressed considerably combined with diminished attention in rhinology, which was limited to the correction of nasal septum deviations, bone injuries, treatment of nasal polyps, and maxillary sinus lavage through the canine fossa [3, 13]. In the middle of the century, the microscopes began to be put into use in nasal operations, introducing a significant success for the operative technique. A higher understanding concerning immunology enabled the medical doctors to distinguish and recognize allergic and non-allergic diseases. An important step regarding the progress of information on the anatomy, physiology, and pathology of paranasal sinuses is attributed to professor Walter Messerklinger and his successor, professor H.  Stammberger, from Austria. Their work about mucociliary activity and ventilation of the anterior ethmoidal cells in addition to the anatomy of the lateral wall of the nose and its mucociliary clearance was crucial to comprehending the drainage and ventilation mechanisms of sinuses [3, 13]. Messerklinger reintroduced nasal endoscopy for diagnostic as well as operative use [3]. Endoscopy received a developmental boost in surgical use through the implementation of novel technologies, in particular when fibre-optic endoscopes began to appear made by the Storz fibre-optic company from 1954 onwards. Coupled with computerized tomography, which Godfrey Hounsfield had brought out in 1969, surgeons from then on could obtain detailed views of the nasal cavity, especially the lateral wall and ostiomeatal unit [3, 13, 19]. Endoscopically guided incision and drainage of the antrum was used to treat treatment-resistant sinusal inflammation by Reynolds and Brandow. David Kennedy, Heinz Stammberger, Wolfgang Draf, and the Brazilian Aldo Stamm all pioneered applications for endoscopy in surgery on the nose and sinuses. Computerized tomography played a large role in furthering the progress of functional endoscopic sinus surgery, as detailed by Kennedy and Zinreich [3, 13]. A neurosurgical application of the endoscope to reach the sphenoid as a way to access the brain was initially undertaken by Gerard Guiot in 1970 at a time when other surgeons, notably Bushe and Halves, were using endoscopy to access the pituitary gland. Prior to that, microscopy guidance had been used. It was Jho and Carrau who led the field in

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performing neurosurgical entry to the brain and resections purely under endoscopic visualization [3, 13]. Rhinology’s appeal was enhanced by the addition of rhinoplasty, hitherto the province of cosmetic surgery, to the work of otorhinolaryngologists. The American Academy of Reconstructive and Facial Plastic Surgery, set up in 1964, and the European Academy of Facial Surgery (Joseph Society), set up in 1977, were the first to do this [23]. Operations on tumours and other lesions affecting the basal area of the skull, as well as brain surgery approached via the nose, provided an area of overlap between ENT and neurosurgeons, just as otology does [23].

2.4

Surgical Progress

Nasal polypi continued to be prominent lesions for discussion into the 1800s. Physicians such as Billroth in 1854 described them as adenomators in nature. In 1863, Virchow called them myxomata, thus describing the so-called “polysaccharide nose”. The legendary Morell Mackenzie in 1884 seemed contented to follow the lead of Virchow [8]. An important treatise on the nasal sinuses was written by J.F.L.  Deschamps (1740–1824) of Paris in 1804 [24]. He wrote about olfaction as a separate entity from the sinuses. He classified nasal polyps as “fungous and vascular, mucous and lymphatic, and scirrhous and sarcomatous”. He talked about a variety of treatment methods including local astringents, excision with a guarded bistoury, evulsion by forceps, the use of knotted thread, chemical caustics, and ligation with silver wire. Prototypes of the polyp snare had been developed by Hippocrates and Fallopius. The concept of the popular Jarvis snare designed in 1880 is still in use for polyp removal by many rhinologic practitioners. At the time of Deschamps, septal deviations were poorly understood, and septal surgery was nonexistent. In 1842, Langenbeck [25] was the first to describe ecchondroses and exostoses of the septum as crests and spurs. What followed was the development of the submucous resection in the early 1900s. In America, Freer [26] described methods to ablate and remove thickened portions of cartilage. He invented a large number of elevators, knives, and forceps to accomplish the task. In almost parallel fashion, Killian [27] elaborated and refined the techniques of septal surgery. The description by Nathaniel Highmore (1613–1685), in 1651 [28], of a case of oral antral fistula after dental extraction, probably led to the development of maxillary sinus surgery. A number of surgeons subsequently developed techniques to trephine the antrum of Highmore. Further perfections in the technique led to the development in the early part of the twentieth century of what we now call the Caldwell-Luc procedure. It was Caldwell of America and Luc of France who independently

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suggested that lesions of the antrum could be approached by making a wide opening in the canine fossa and a counter opening into the nasal cavity through the inferior meatus [29, 30]. For the ethmoid and frontal sinuses, external approach surgery can be associated with the names of Lynch of New Orleans and Howarth of London, who in 1921 described techniques to enter these sinuses without leaving unsightly scars or bony deformities [31, 32].

2.4.1 History of Septoplasty –– 3500  BC: The Ebers Papyrus, containing the very first known reference to rhinologic surgery, was noted during this time period in Egypt. Many of the procedures mentioned in it were reconstructive since rhinectomy was a frequent type of punishment [33]. –– 1757: Quelmatz was amongst the foremost physicians to manage septal deformities. His advice was digital pressure on the septum on a daily basis [33]. –– 1875: Adams proposed fracturing and splinting of the septum [33]. –– Late nineteenth century: The most popular procedure in the USA was the Bosworth operation to treat nasal blockage due to nasal septal deviation. Using a customized saw, the deviation was trimmed combined with the associated mucosa. Outcomes were suboptimal [33]. –– 1882: Ingals presented en bloc resection of smaller sections of septal cartilage. As a result of this advancement, he is ascribed as the father of modern septal surgery. Around the same period, cocaine was starting to be widely used in operations. With its advent, anaesthesia and homeostasis for nasal surgery improved considerably. Lengthier and technically more enhanced procedures became possible [33]. –– 1899: Asch was the first to recommend modifying the tensile curve of septal cartilage rather than resecting it. He suggested using full-thickness cruciate incisions [33]. –– 1902 and 1904: Freer and Killian defined the submucous resection (SMR) operation. This procedure is the cornerstone of modern septoplasty methods. They recommended elevating mucoperichondrial flaps and resecting the cartilaginous and bony septum (which includes the vomer and perpendicular plate of the ethmoid), keeping 1  cm dorsally and 1 cm caudally to sustain support [33]. –– 1929: Metzenbaum and Peer were the first ones to operate the caudal septum, using a number of different techniques. The traditional SMR was much less efficient in repairing this area of deviation. Moreover, Metzenbaum recommended the application of the swinging door technique, and in 1937, Peer suggested taking out the caudal septum, straightening it, and then relocating it in midline position [33].

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–– 1947: Cottle presented the hemitransfixion incision and the process of conservative septal resections. Long-term follow-up reports of individuals who were operated with the SMR technique mentioned dorsal saddling, retraction of the columella, and alar widening from time to time; thus, conservative resections during septoplasty were planned to prevent these complications [33].

2.4.2 The Sinus Revolution Sinus operations arise most likely from the period of the New Kingdom of ancient Egypt. Instruments had been used to take out the brain via the nasal route within the mummification procedure. The curiosity for the pathology of the maxillary sinus began to gain popularity in the seventeenth century. Antral trephination for suppuration was a widespread procedure in those days. An oroantral fistula was usually produced through the removal of a molar for the drainage of the infected maxillary sinus everyday [34]. The maxillary sinus was initially accepted clinically in the sixteenth century and its function as the cause of supuration grew to be the centre of interest. Efforts to drain and ventilate this readily accessible sinus started with Nathaniel Highmore in 1651 and proceeded throughout the twenty-­ first century. The initial draining of the sinus was accomplished via various kinds of routes, such as the alveolar margin, anterior wall, and middle and inferior meati [35]. Afterwards, the anterior wall of the maxillary sinus was exposed through the canine fossa and was maintained patent for lavage. Caldwell (1893), Scanes Spicer (1894), and then Luc in 1897 sealed the canine fossa incision following an intranasal antrostomy and the stripping of the infected mucosa [19]. Ever since the 1600s, surgeons have paid attention to the maxillary sinus, which is both large and easy to approach. Its role in sinusitis was suspected from ordinary roentgenography. Endoscopic views and CT scans, in the hands of pioneering surgeons, such as Zuckerkandl, confirmed that the maxillary sinus and ostiomeatal unit were implicated in long-standing infections of the nose and sinuses [35]. The way long-standing infections of the nose and sinuses are treated has been revolutionized by scientific and technological advances. Nasal telescopes, comprising a single lens in a rigid metallic tube and utilizing fibre optics, led to advances in viewing the nasal cavity and sinuses. The invention of the rod lens by Prof. Harold Hopkins in 1954 led to obsolescence of the older types and was the curtain raiser on a new era for endoscopy. Mucociliary motion and coordination were researched by the Austrian, Prof. Walter Messeklinger, who focused on the nasal cavity and sinuses. King had actually already shown that mucus travels upwards towards the meatal ostium, even when a wide exci-

2  History of Rhinology

sion has been made lower down in the sinus. Messerklinger’s 1967 research showed that the function of the mucociliary escalator is genetically determined and mucus converges towards the ostium. If the drainage through the ostium were impaired, recurrent sinusitis would ensue. His research highlighted the pivotal role of the anterior ethmoid and ostiomeatal unit in understanding the pathogenesis of chronic (recurrent) sinusitis. First Messerklinger in Austria (1978) and then Draf in Germany (1983) propagated their experience in endoscopy of the nose, stressing its role in reliable diagnostic practice and how it could assist surgery on the sinuses [22]. CT and multiangle endoscopy paved the way for operations of a less invasive and radical kind, with an improvement in clinical functional outcome, since they worked in harmony with pre-existing physiological clearance of the sinuses. Knowing that otorhinolaryngologists are already familiar with operative microscopy, Draf suggested both could be combined and leave the hands free at the initial stage of a procedure. He advocated allowing the endoscope to penetrate deeply within the nose where complex procedures were being undertaken. A further advance he made was in the application of non-invasive methods to treat disorders of the base of the skull, an example being Draf I, II, and III, which permit the frontal sinuses to maintain their original pattern of mucous clearance via the ostia. Subsequently, Prof. H Stammberger helped to make the technique better known and wrote about his work using the technique in endoscopic sinus surgery in 1991 [22].

2.4.3 History of Rhinoplasty 2.4.3.1 History of Endonasal (Closed) Rhinoplasty The history of nose surgical procedures is actually extensive. The Edwin Smith operative papyrus of the ancient Egypt describes the diagnosis and treatment of nasal deformities several 30 centuries earlier [34]. In roughly 800 BCE, Sushruta of India defined a nasal reconstruction technique by transferring a pedicled forehead skin flap [36]. In the sixteenth century, Tagliacozzi of Bologna, Italy, applied brachial-­based delayed flaps for reconstructing noses. The art and science of rhinoplasty continued to be basically at a standstill before the nineteenth century. Techniques that can correct nose deformities were utilized by earlier plastic surgery pioneers including Dieffenbach around 1840s, who applied a buried forehead flap for covering the dorsum of nose [37]. The earliest record of a contemporary endonasal rhinoplasty was published by the American otolaryngologist, John Orlando Roe. The original report released in 1887 was entitled “The deformity termed ‘pug nose’ and its correction

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by a simple operation” and explained the management of saddle nose deformities [38]. In 1892, Robert F. Weir, a different US operating doctor, likewise shared his techniques for repairing the saddle nose [39]. In 1898, Jacques Joseph, an orthopaedic specialist, revealed his innovative ideas of nose surgery to the Medical Society of Berlin. Numerous ambitious rhinoplasty surgeons visited Germany to watch Joseph carry out his rhinoplasties. His traditional name as the father of modern rhinoplasty may be recognized by his impact in shaping a lot of rhinoplasty principles and techniques. Actually, the majority of the fundamental rhinoplasty manoeuvres continue to be basically identical today as Joseph initially defined them. Joseph’s principles and techniques were furthermore outspread (especially in the USA) by specialists including Gustav Aufricht, Joseph Safian, and Samuel Fomon. Fomon’s teachings and medical review classes concerning endonasal rhinoplasty assisted in the training of numerous young rhinoplasty surgeons, such as Maurice Cottle of Chicago and Irving Goldman of New York [40]. In the rather brief past of modern rhinoplasty, numerous other rhinoplasty experts have assisted in the development of the techniques. Many surgeons contribute to improve our knowledge of the art and science of rhinoplasty. This ongoing sharing of information about rhinoplasty has perhaps rewarded both the patient and the surgeon [40].

2.4.3.2 History of External (Open) Rhinoplasty The Ebers Papyrus of Egypt (from ~3500 BCE) contained a dialogue about nose reconstruction for rhinectomy, a punishment in ancient Egypt. In 800 BCE, Sushruta carried out nose reconstruction using a pedicled forehead flap. In the 1500s, Tagliacozzi reported delayed arm-based flaps for nose reconstruction. In the 1750s, Quelmatz recommended day-to-day digital pressure for septal deformities. In 1845, Dieffenbach performed external skin cuts to alter the shape of the nose. In 1887, Roe executed the initial cosmetic rhinoplasty, secondary to a pug nose deformity [41]. In the beginning of the twentieth century, Killian and Freer created submucous resection septoplasty. Peer and Metzenbaum executed the first manipulation to the caudal septum in 1929. In 1947, Cottle carried out a hemitransfixion incision along with the conservation of the septum and turned out to be a strong promoter of the closed approach. In the 1990s, Sheen enhanced his initial theories and encouraged the closed approach as well [41]. Regarding open rhinoplasty, Rethi firstly presented the columellar incision for open rhinoplasty for tip modification in 1921 [42]. In 1957, Sercer used the open approach to reach the nasal cavity and septum through a columellar incision and named the method “nasal decortication”. In the following 15 years, open rhinoplasty lost its popularity up till Padovan presented his series in the early 1970s,

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C. Cingi et al.

suggesting open rhinoplasty. Moreover, in the 1970s, Goodman furthermore presented the case for the open approach [43]. In 1982, Anderson et al. [44] also published a paper on open approach. In the 1990s, Gunter started to be a supporter of the open rhinoplasty [45]. Currently, the discussion still goes on about the advantages and disadvantages of an open versus closed approach to rhinoplasty [45–49].

2.4.4 H  istory of Cerebrospinal Fluid Rhinorrhea From the first intracranial repair in the 1900s to the use of endoscopes and image guidance systems, the management of cerebrospinal fluid (CSF) rhinorrhea has greatly evolved. Dandy is credited with the first surgical repair of a CSF leak via a frontal craniotomy approach in 1926. Various other authors, including Dohlman (1948), Hirsch (1952), and Hallberg (1964), subsequently reported successful repair of CSF rhinorrhea through different external approaches. In 1981, Wigand reported on the use of the endoscope to assist with the repair of a skull base defect. Since then, endoscopic repair has become the preferred method of addressing CSF rhinorrhea, given the high success rate of 90–95% and the decreased morbidity associated with this approach [50].

2.5

Towards the New Millennium

At the turn of the century, rhinology was developing under the tutelage of various individuals, including Arthur W.  Proetz, professor of ENT surgery at Washington University, St Louis, Missouri, who wrote an article entitled, “The Displacement Method of Sinus Diagnosis and Treatment”, which garnered him the 1931 Castlebury Prize of the American Laryngological Association [51]. He described a principle of displacement, whereby air could be evacuated from the sinusal spaces via the nostrils, the resulting partial vacuum being dispelled when a fluid at the ostium is aerosolized and enters the sinuses on the release of negative pressure. With only a relatively crude operative setup, and by placing the head in various attitudes, he could both determine the disorder and provide therapy for the the entire range of sinus disorders, both chronic and acute. Another individual prominent in the field in the last century was Professor O.E. Van Alyea of the University of Illinois in Chicago was also a pioneer in rhinology field. He wrote the seminal textbook on the nasal sinuses in 1941 and considered as the world expert on disorders of the sinonasal. The book took into account the burgeoning fields of nasal physiology and anatomy, and the increasing degree to which aller-

gic conditions were taking centre stage in studies of sinonasal disease, with expositions of emerging concepts such as the mucociliary blanket, mucositis secondary to allergy, and the medications then coming into use, such as the first antibiotics. Another important figure of the twentieth century was Professor O.E. Van Alyea from the University of Illinois in Chicago. He was considered by many to be the authority on nasal and sinus disease. He offered a landmark textbook in 1941 entitled Nasal Sinuses [52]. He based his book on the rapidly increasing knowledge of nasal physiology, anatomy, and a growing importance of the role of allergy as the cause of nasal and sinus conditions. The book described newer concepts such as the mucociliary blanket, mucosal inflammation caused by allergy, and pharmacotherapy, including the use of newly discovered antibiotics to treat sinus infections. Maurice H.  Cottle (1898–1981), within the last few decades, was so significant a figure as to have been described widely as the “rhinologist of the century”. His work set rhinology on an equal footing with otology and laryngology. He both taught and innovated, preferring surgical methods that preserved functional anatomy and becoming highly expert on the lateral nasal wall and its anatomical composition, as well as refining rhinomanometry as a technique capable of providing quantifiable physiological information to surgeons [1]. The American Rhinologic Society, which was established under his leadership in 1954, remains a vibrant society. Many of his concepts used in teaching are referred to as “Cottleisms” [1].

2.6

Modern Era

Rhinoplasty as currently understood can trace its origins not, as might be expected, to an otorhinolaryngologist but rather to the Berlin-based orthopaedic specialist Jacques Joseph, a surgeon who was not particularly outstanding amongst his peers but who made great strides in how rhinoplasty was viewed. Reduction rhinoplasty, for nasal humps and related deformities, was outlined carefully by him, as were the psychosocial elements requiring attention before contemplating rhinoplasty. His inventiveness extended as far as the development of several surgical instruments which remain in use to this day. He published a superbly detailed account of how the nose could be corrected operatively and put intranasal rhinoplasty on a sound scientific footing in the early 1900s. A 1928 book which dealt in detail with rhinoplasty was due to him. At the same period, the New Yorker John Roe was refining surgical approaches that emphasized correction more than reconstruction. The popularity of the transcartilaginous approach in the reduction of nasal bulbosity owes much to his work [22].

2  History of Rhinology

2.7

History of Antibiotics

2.7.1 Early History In the classical era: –– Fungi and medicinal plants were put onto the sites of infections with curative intent. –– Bread that was sprouting mould found application in cases of both injury and infection in Ancient Greece and Macedonia. –– Russian Peasant medicine advocated the application of heated earth to suppurating wounds. –– In the ancient Sumer, a potage composed of beer, the shell of chelonians, and snake skins was administered by healers. –– Turned milk and bile taken from frogs was an opthalmic treatment in Ancient Babylonia. –– In Ceylon, soldiers used sweetmeats (oil cake) to dry wounds and combat bacterial infection [53].

2.7.2 Modern History –– 1640: The Englishman Parkington advocated fungi for therapeutic usage in his pharmacopoeia. –– 1870: Sir John Scott Burdon-Sanderson, working in England, found that mould could inhibit the growth of bacteria on culture media. –– 1871: Lister (England) researched whether Penicillium glaucium (so named) had effects on human tissues infected with bacteria, and then in 1875 Tyndall presented to the Royal Society his findings on the ability of Penicillium genus moulds to halt bacterial growth. –– 1877: Pasteur, a Frenchman, suggested that some bacterial species had a bactericidal capability themselves, such as anthrax. –– 1897: Duchesne in France was able to treat typhoid in guinea pigs using topically applied P. glaucium. –– 1928: Sir Alexander Fleming in England isolated the lysozyme enzyme together with the penicillin molecule responsible for P. notatum’s bactericidal ability. –– 1932: Gerhard Domagk, based in Germany, discovered Sulfonamidochrysoidine (Prontosil). –– 1940s–1950s: Selman Waksman coined the term “antibiotic” for the antimicrobial agents streptomycin, chloramphenicol, and tetracycline, discovered at that time.

2.7.2.1 Sir Alexander Fleming The isolation of lysozyme in 1921 and penicillin in 1928 by the biologist Sir Alexander Fleming, a Scot, were landmark events in the quest for modern antimicrobials. Penicillin extracted from P. notatum revolutionized bacterial chemotherapy of such disorders as syphilis, gangrene, and tubercu-

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losis. In a similar vein, medicine owes a profound debt to his bacteriological, immunological, and chemotherapeutic studies. Studies that he undertook in the course of military service paved the way for his isolation of the naturally occurring lysozyme (a name due to Fleming), a substance with antiseptic properties. It was discovered that lysozyme is expressed by tissues and contained in mucus, tears, and egg albumen. The most severe pathogens were, however, resistant to lysozyme. More by luck than design, 6 years after the discovery of lysozyme, he chanced upon penicillin, after noting how a culture medium contaminated with the widely prevalent mould, P. notatum, no longer supported staphylococcal colony growth. Further investigation revealed the fact that a soluble substance released by P. notatum was responsible for this zone of inhibition. When isolated as penicillin (Fleming’s own nomenclature), the activity was retained even when in concentrations 800 times less than when first isolated [53]. For this profound achievement, which altered the face of modern medicine, he became both a knight in 1944 and a Nobel Prize recipient (physiology or medicine) the following year [53].

References 1. Frenkiel S, Wright ED. The specialty of rhinology, part 1: a historical glimpse. J Otolaryngol. 2001;30(Suppl 1):26–31. 2. Leopold D. A history of rhinology in North America. Otolaryngol Head Neck Surg. 1996;115:283–97. 3. Stammberger H.  History of rhinology: anatomy of the paranasal sinuses. Rhinology. 1989 Sep;27(3):197–210. 4. Nogueira JF Jr, Hermann DR, Américo Rdos R, Barauna Filho IS, Stamm AE, Pignatari SS.  A brief history of otorhinolaryngolgy: otology, laryngology and rhinology. Braz J Otorhinolaryngol 2007 Sep-Oct;73(5):693–703. 5. Lascaratos JG, Segas JV, Trompoukis CC, Assimakopoulos DA. From the roots of rhinology: the reconstruction of nasal injuries by Hippocrates. Ann Otol Rhinol Laryngol. 2003;112(2):159–62. 6. Papyros Ebers, ubersetzt von Dr. Med. H. Joachim, Berlin, 1890. 7. Wright J. A history of laryngology and rhinology. Philadelphia: Lea and Febiger; 1914. 8. Stevenson RS. Guthrie D. a history of Oto-laryngology. Edinburgh: Livingstone; 1949. 9. Voltolini FER. Die Krankheiten der Nase. Breslau, 1888. 10. Hippocrates. Works translated and edited by Jones WHS and Withington ET. London: Loeb Classical Library, 1923. 11. Celcus OC. De medicina. Spencer WG, trans. London: Loeb classical library, 1935–38. 12. Galen C. Works translated and edited by Brock AJ. London: Loeb classical Library, 1916. 13. Feldmann H.  The maxillary sinus and its illness in the history of rhinology. Images from the history of otorhinolaryngology, highlighted by instruments from the collection of the German medical history Museum in Ingolstadt. Laryngorhinootologie. 1998;77(10):587–95. 14. Vesalius A. De humani corparis fabrica. Venice, 1543. 15. Fallopius G. Observationes anatomicae. Venice 1561. 16. Forestus P. Observationum et curationum medicinalium libri. Ludg. Batar, 1591. 17. Willis T. De cerebri anatome, London, 1664.

32 1 8. Schneider CV. Liber primus de catarrhis. Wittenberg, 1660. 19. Tange RA. Some historical aspects of the surgical treatment of the infected maxillary sinus. Rhinology. 1991;29(2):155–62. 20. Türkiye'nin İlk Rinoloji Kitabı (Turkey's First Book of Rhinology). Rinoturk-Tanyeri. Turkish Rinologic Society. http://www.rinoturk. org/index.php?option=com_content&view=article&id=61:tuerki yenin-lk-rinoloji-kitab&catid=35&Itemid=57. Accessed 20 Aug 2015. 21. Lasmar A, Seligman J. História (e histórias) da Otologia no Brasil. Revinter; 2004. 22. Kaluskar SK.  Evolution of rhinology. Indian J Otolaryngol Head Neck Surg. 2008;104(60):101–5. 23. Weir N. History of medicine: otorhinolaryngology. Postgrad Med J. 2000;76:65–9. 24. Deschamps JFL. Dissertation sur les maladies des fosses nasales. Paris, 1804. 25. Langenbeck. Handbuch der Anatomie, Gottingen, 1843. 26. Freer O. The correction of deflections of the nasal septum with a minimum of traumatism. JAMA. 1902;38:636. 27. Killian G. Die submucose Fensterresektion der Nasenscheidewand. Arch Larang Rhinol (Berl). 1904;16:362. 28. Highmore N. Corporis humani disquisitio anatomica. The Hague, 1651. 29. Caldwell GW. N Y Med J. 1893;18:527. 30. Luc H. Arch internat De laryng. 1897;6:216. 31. Lynch RC. South Med J. 1924;17:289. 32. Howarth W. J Laryngol Otol. 1921;36:417. 33. Watson D.  Septoplasty. In: Meyers AD (Ed.). Medscape. http:// emedicine.medscape.com/article/877677-overview#showall. Accessed 20 Aug 2015. 34. Goldwyn RM. Is there plastic surgery in the Edwin smith papyrus? Plast Reconstr Surg. 1982;70(2):263–4. 35. Lund V. The evolution of surgery on the maxillary sinus for chronic rhinosinusitis. Laryngoscope. 2002;112(3):415–9. 36. Sushruta. Sushruta Samhita (English translation by K.L.  Bhishagratna). 1998. Calcutta, India: Kaviraj Kunjalal Publishing; 1907–17. 37. Dieffenbach JF.  Die operative Chirurgie. Liepzig, Germany: F.a. Brockhaus; 1845.

C. Cingi et al. 38. Roe JO. The deformity termed “pug-nose” and its correction, by a simple operation, vol. 31. New York: The Medical Record; 1887. p. 621. 39. Weir RF.  On restoring sunken noses without scarring the face. New York: The Medical Record; 1892. 40. Vartanian AJ.  Basic closed rhinoplasty. In: Granick MS (ed) Medscape. http://emedicine.medscape.com/article/1291976overview#a6. Accessed 20 Aug 2015. 41. Arneja JS. Basic open rhinoplasty. In: Granick MS (ed) Medscape. http://emedicine.medscape.com/article/1292131-overview#a7. Accessed 20 Aug 2015. 42. Rethi A. Operation to shorten an excessively long nose. Rev Chir Plast. 1934;2:85. 43. Goodman WS, Charles DA.  Technique of external rhinoplasty. J Otolaryngol. 1978;7(1):13–7. 44. Anderson JR, Johnson CM Jr, Adamson P.  Open rhinoplasty: an assessment. Otolaryngol Head Neck Surg. 1982;90(2):272–4. 45. Gunter JP.  The merits of the open approach in rhinoplasty. Plast Reconstr Surg. 1997;99(3):863–7. 46. Aiach G.  Atlas of rhinoplasty: open and Endonasal approaches, second edition. Plast Reconstr Surg. 2005;115(6):1778–9. 47. Sheen JH. Closed versus open rhinoplasty--and the debate goes on. Plast Reconstr Surg. 1997;99(3):859–62. 48. DeFatta RJ, Ducic Y, Adelson RT, Sabatini PR.  Comparison of closed reduction alone versus primary open repair of acute nasoseptal fractures. J Otolaryngol Head Neck Surg. 2008;37(4): 502–6. 49. Anderson JR.  The future of open rhinoplasty. Facial Plast Surg. 1988;5(2):189–90. 50. Welch KC.  CSF Rhinorrhea. In: Meyers AD (Ed.). Medscape. http://emedicine.medscape.com/article/861126-overview#a5. Accessed 20 Aug 2015. 51. Proetz AW. The displacement method of sinus diagnosis and treatment. St. Louis: Annals; 1931. 52. van Alyea OE. Nasal sinuses. Baltimore: Lippincott, Williams and Wilkins; 1951. 53. History of antibiotics. https://explorable.com/history-of-antibiot ics. Accessed 7 Apr 2016.

3

Histology and Embryology of the Nose and Paranasal Sinuses İsa Azgın, Murat Kar, and Emmanuel P. Prokopakis

3.1

Introduction

A precise comprehension of the growth and anatomical variances of the nasal septum and components of the lateral nasal wall is crucial for the best management of nasal blockage. With the understanding of the particular area and anatomical explanation for an individual’s nasal blockage, physicians can better determine the precise composition that is accountable for the blockage and hence carry out a better focused strategy to treat the condition [1]. In this chapter, the embryology and histology of the nose and paranasal sinuses will be presented.

3.2

Embryology of the Nose and Paranasal Sinuses

3.2.1 Fetal Facial Formation The stomodeum is called the rudimentary mouth which develops around the fourth week of the fetal period, in the center of the place between the first pharyngeal arches which gives rise to the facial structures. The neural crest cells of pharyngeal arches interact to form the skeleton, while the mesoderm produces the muscles of the face and neck. Around the fifth week of the fetal period, the face starts to form, beginning with the nasal placodes which form the nasal pits after they evaginate. The primordial lip is formed by the frontal nasal prominences which appear over the sto-

İ. Azgın (*) Department of Otorhinolaryngology, University of Health Sciences, Konya Training and Research Hospital, Konya, Turkey M. Kar Department of Otorhinolaryngology, Kumluca State Hospital, Antalya, Turkey E. P. Prokopakis Department of Otorhinolaryngology, University of Crete School of Medicine, Crete, Greece

modeum. The union of the mandibular prominences gives rise to the origins of the lower lip, chin, and mandible [2]. The nose is formed by the fusion of five different prominences: the frontal prominence which gives rise to the bridge of the nose; the two medial nasal prominences which give rise to the crest, tip and central portion of the lip, or intermaxillary segment; and the lateral nasal prominences create the sides. It is essential that the medial nasal prominences fuse completely since the contrary can result in a cleft lip or palate [3]. Then, in the seventh week, the nasolacrimal groove and duct are formed. The nasolacrimal duct drains the extra tears from the conjunctiva into the nose [4]. Through the sixth and seventh week, the upper lip starts to develop as the nasal and maxillary processes broaden and unite with each other. The lower lip starts to develop actually before the upper lip as the mandibular swellings unite continuously, and the depression of the mandible is packed “by proliferation of mesenchyme.” The buccopharyngeal membrane “ruptures to form a broad, slitlike embryonic mouth” and does not acquire its last form before the middle of the second month, when the “maxillary and mandibular swellings generate the cheeks” [4]. Robinow syndrome, or fetal face syndrome, is an uncommon genetic condition which leads to anomalies of the face that look as if the fetal development is not fully completed. The head is bigger and the forehead is shaped abnormally and bulging. The nose is smaller and deformed, with flared nostrils along with a sunken bridge. The eyes can be quite widespread. Additional anomalies related to other parts of the body are also seen [2].

3.2.2 Formation of the Primary and Secondary Palates The palate is actually derived from two primordia named as the primary and secondary palates. The primary palate develops from the medial nasal process beginning at the sixth

© Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_3

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week of the fetal period. A “wedge-shaped mass” derived from the mesoderm lengthens to create the floor of the nasal cavity [5]. The secondary palate starts to form from the lateral palatine processes at the eighth or ninth week of development; however, its formation is not finished before the third month. The lateral processes expand vertically on the sides of the tongue; then as the oral cavity is formed, “the tongue moves inferiorly,” and the lateral processes shift upward and towards one another to merge [5]. The mandible is also formed along with the formation of the oral cavity. The merging of these palatine processes requires a serious force; however, the origin of this force is not known. Several physiological transformations which occur during this period of fetal development were linked to this phenomenon. One of the reasons proposed as the origin of this force is “the progressive accumulation and hydration of hyaluronic acid” [6]. During this phase of development, a substantial rise in the concentration of glycosaminoglycans is observed “which attract water and make the shelves turgid.” Moreover, “the presence of contractile fibroblasts in the palatine shelves” is likely to be involved in producing an intrinsic force which is essential to press the two processes to each other enabling them to fuse [7]. The particular stages of the development of the tongue and head are related to this formation. For the processes to fuse, two layers of epithelial cells line up and join each other with a seam in the midline. Prior to the fusion, synthesis of DNA halts for a minimum of 24 h, and the epithelial cells go through a physiologic apoptosis and the basal epithelial cells become uncovered. Junctions are created, and the seam which develops at the junction will be made up of two epithelial cell layers which should ultimately come to be one whenever “the growth of the seam fails to keep pace with palatal growth so that the seam first thins to a single layer” [7]. Palatal merging is accomplished near the twelfth week, once the midline seam fades away fully. Then, the epithelial cells start to differentiate creating different components of the palate. The cells turn into pseudostratified ciliated columnar epithelium on the nasal side while they turn into stratified squamous, nonkeratinizing epithelium on the oral side. Once “ossification occurs in the anterior two-thirds of the palate,” the hard palate develops, but the soft palate develops as ossification does not take place in its location. If the cells in this location do not distinguish properly, complications like a cleft palate may arise [8]. The development of maxilla starts from the location where the anterosuperior dental nerve and inferior orbital nerve separate. Its development is related to the cartilage which creates the nasal capsule. Nevertheless, the maxilla has an extra cartilage, the zygomatic cartilage, that plays a part in its development. Bone development proceeds anteri-

İ. Azgın et al.

orly and posteriorly, while grooves are created to hold the nerves and tooth germs within the mandible. The ossification of the hard palate takes place within this period. The maxilla gets bigger in size after being born due to the enlargement of the maxillary sinuses [7].

3.2.3 D  evelopment of the Nasal Cavities and Sinuses 3.2.3.1 Development of the Nasal Cavities The formation of the nasal cavity takes place in the sixth gestational week. Deepening of the nasal pits results in the development of the primitive nasal cavity, which is divided from the primitive oral cavity by the oronasal membrane [9]. Primitive choanae link the oral and nasal cavities right in the back of the primary palate. When the secondary palate develops, the final choanae appears at the intersection of the nasal cavity and pharynx. Simultaneously, the turbinates (upper, middle, and lower) develop from the lateral wall of the nose. The septum of the nose develops from the merged nasal processes and extends inferiorly combining with the palatine shelves. The ectodermal coating over the roof of the nasal fossa converts to olfactory epithelium, with several cells distinguishing to olfactory receptors (neurons) as their axons turn into olfactory nerves. The axons of the neurons propagate into the olfactory bulb in the frontal cortex. Postnatally, the size of the nasal fossa gets bigger rapidly. Through the initial year of life, the total minimum cross-sectional area grows by 67%, while the volume of the anterior 4 cm of the nasal airways grows by 36% as recorded by acoustic rhinometry. These numbers are bigger in men; but if adapted for the variations of body dimensions, variation among men and women is gone. As a result, the dimensions of the nasal airway are not based upon gender but are simply related to bodily proportions. The most remarkable relationship was identified among the dimensions of the airways and the head circumference [9, 10]. The nasal prominences develop close to the nasal placodes and will “form the floors of depressions called nasal pits” that merge within the sixth week becoming a solitary sac. Initially, the oronasal membrane detaches the oral and nasal cavities; however, anytime it breaks, these cavities will be joined. The primordial choanae are “the openings between the nasal cavity and nasopharynx” [5]. Concurrently, while the secondary palate develops, the septum of the nose starts to develop from the frontal nasal and the medial nasal processes. The nasal septum expands downward towards the primary and secondary palates to separate the nasal fossa into two airways, “which open into the pharynx behind the secondary palate through an opening called the definitive choana” [4]. The olfactory epithelium develops from the specialization epithelial cells on top of the nasal fossa. “Some

3  Histology and Embryology of the Nose and Paranasal Sinuses

epithelial cells distinguish to olfactory receptor cells ­(neurons). The axons of these cells make up the olfactory nerves (cranial nerve I) and become the olfactory nerves of the brain” [5]. Nasoseptal Embryology The face and nasal structures originate from three distinct embryonic sources: the ectoderm, the neural crest, and the mesoderm. The ectoderm produces an overlying cover and a pattern for creating structures as a result of its communications with mesenchymal layers. Neural crest cells deliver most of the mesenchyme of the face which supplies precursors for myoblasts that distinguish into voluntary muscles of the craniofacial area [1, 11–13]. During the fourth gestational week, five primordial structures are identified surrounding the stomodeum, a depression beneath the growing brain and face. These five structures are the frontonasal prominence and the two maxillary and mandibular prominences. As the fourth gestational week ends, paired thickenings of ectoderm show up on the frontonasal prominence superior and lateral to the stomodeum [1, 11–14]. In the fifth week, mesenchymes on the periphery of the nasal placodes multiply to create horseshoe elevations. The lateral and medial limbs are named as nasolateral and nasomedial processes, respectively. The mesenchyme around the nasal placodes keeps proliferating and thickening, thus causing a recognizable depression of the placodes. These depressions are eventually called the nasal pits and are the primordia of anterior nares and nasal cavities [1, 11–14]. By the fifth gestational week, the nasal pits keep on deepening towards the oral cavity. Through the six to eight weeks, just a slim oronasal membrane stands between the oral cavity and nasal cavities [1, 11–14]. Then this oronasal membrane decomposes, resulting in a connection to the nasal cavities behind the primary palate. The connecting areas are called the primordial choanae. When the palatal shelves merge with the development of the secondary palate, the nasal cavity elongates, creating a junction between the nasal cavity and pharynx [1, 11–14]. Between the fourth and sixth gestational weeks, the two maxillary processes expand medially towards one another and towards the two nasomedial processes [1, 11–14]. As the sixth week ends, the nasolateral processes start merging with the maxillary processes to create the ala nasi and the lateral border of the nostril. The nasolacrimal grooves are formed around the intersections of the nasolateral and maxillary processes. The ectoderm in the nasolacrimal grooves gets thicker forming the epithelial cords that divide and generate the nasolacrimal duct and lacrimal sac. Towards the end of the gestation, nasolacrimal ducts lengthen the medial sides of the eyes towards the inferior meatuses in the lateral side of the nasal fossa [1, 11–14].

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The nasomedial prominences keep on growing yet stay unfused till the seventh to eighth gestational week, as they unite with superficial parts of the maxillary processes. The synthesis creases among these processes are nasal fins. While mesenchymal cells enter this connection, a steady merging is created, filling out most of the upper lip and jaw. The nasomedial processes subsequently combine with one another, creating the intermaxillary segment and eventually moving the frontonasal prominence posteriorly. The intermaxillary portion which is produced from the nasomedial processes is the precursor to numerous structures, such as the primary palate, the nasal tip and crest as well as a part of the septum of the nose [1, 11–14]. The nasal septum expands downward from the nasofrontal prominence to the palatal shelves, along with the merging of these structures creating the secondary palate. Anteriorly, the septum is continuous with the primary palate formed by the nasomedial processes. The fusion of the palate develops posteriorly to the incisive foramen and elongates anteriorly and posteriorly. The incisive foramen is the fusion place between the primary and secondary palates [1, 11–14]. Embryogenesis of the Nasal Cavity and Palate In the final phases of the formation of the nasal area, the nasal septum separates the nasal cavity to two compartments. The components of nasal septum are the quadrangular cartilage, the perpendicular plate of the ethmoid bone, the vomer, the crest of the maxillary bone, the crest of the palatal bone, and the membranous septum [1, 11–14]. The tubular vomeronasal organ initially comes out as two epithelial thickenings on the septum. Until the fortieth gestational day, this primordial organ has penetrated the septum. Enclosed in a blind pouch, this organ later detaches from the septal epithelium. In different species, the vomeronasal organ is covered with chemoreceptors, much like the ones in the olfactory epithelium. This epithelium extends to the accessory olfactory bulb that links to the amygdala and other limbic centers [1, 11–14]. Lateral Nasal Wall Embryology At the eighth gestational week, a cartilaginous nasal capsule envelopes the nasal fossa and proceeds with septal cartilage. Three soft tissue elevations or preturbinates are recognized inside the nasal cavity. Although it is quite an early period, these preturbinates are similar to the adult inferior, middle, and superior concha in dimension and location [1, 11–14]. During the ninth to tenth week, the cartilage capsule grows into two cartilaginous flanges which enter into the soft tissue elevations of the inferior and middle conchae. A little elevation of cartilage placed in the front of the middle meatus eventually creates the uncinate. This cartilage is generated medially from the lateral cartilage capsule. When the uncinate process starts to be formed, a crest of bone coming from

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the hard palate proceeds posteriorly to take the place of the lateral cartilaginous capsule and develops into the nasal wall posterolaterally [1, 11–14]. In the eleventh and twelfth weeks, the primordial ethmoidal infundibulum builds up in an area lateral to the uncinate in the middle meatus. A small pathway going inferolaterally towards the precursor of maxilla within this place is the primary growth of the maxillary sinus. When the primordial maxillary sinus develops, a vertical plate of bone advancing from the primitive maxilla elongates posteriorly to set the lower part of the orbit apart from the lateral cartilaginous capsule. Furthermore, a second vertical bony plate lengthens cephaladly from the hard palate and makes up the posteroinferior lateral wall of the nasal fossa [1, 11–14]. At the fifteenth to sixteenth week, the inferior, middle, and superior conchae are quite developed. Furthermore, the primordial maxillary sinus is enclosed by a sleeve of cartilage and develops from the area lateral to the uncinated process, the infundibulum of ethmoid, inferiorly towards the apex of maxilla. Posterior protrusions from the infundibulum of ethmoid keep on enlarging and will turn out to be the posterior ethmoid cells [1, 11–14]. During the seventeenth to eighteenth week, the dense cartilage cover of the primitive maxillary sinus produces continuous extensions of the sinus, inferiorly, laterally, and anteriorly. This channel extends medial to the nasolacrimal duct close to its starting point from the eye. The primary ossification of the precursor cartilage of the inferior concha takes place at the point where this structure buds from the lateral cartilaginous capsule. Posterior protrusions into the sphenoid bone are seen [1, 11–14]. Within the subsequent 3–4 weeks, ossification continues to include the superior part of the nasolacrimal duct close to the eye and the middle concha. Like the inferior concha, the ossification of the middle concha begins at its origin from the lateral cartilaginous capsule [1, 11–14]. At the twenty-fourth gestational week, the primordial maxillary sinus invaginates into the maxillary bone. On the lateral side, a plate of bone divides the channel from the eyeball, and on the medial side, the plate divides the inferior concha from the lateral cartilaginous capsule. Also, the nasolacrimal duct is tightly surrounded in a tube of bone cranially close to the orbit [1, 11–14]. The growth of the lateral wall of the nose is nearly finished by the twenty-fourth gestational week. Until this week, the superior and middle conchae have been created and ossified from the ethmoidal bone, while the inferior concha has come out from the maxillary bones and the lateral cartilaginous capsule. Depending on the very first thickening of the mucosa, conchal growth seems to be a primary development, while the meatal ingrowth takes place secondarily [1, 11–14].

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3.2.3.2 Development of the Paranasal Sinuses The growth of the face and all of the components of the viscerocranium are established by the growth of paranasal sinuses. Actually, when the sinuses are not present, the components of the face are smaller in comparison to the neurocranium. As the paranasal sinuses enlarge, the growth of the entire face is affected, and the face eventually acquires its finalized appearance [9]. The initial indicators of the growth of the maxillary sinus are obvious around the tenth week as a pouch in the lateral wall of the infundibulum of ethmoid. From delivery, the maxillary sinus is almost 8 mm in depth, 4 mm in width, and 3 mm in height. Growing proceeds following delivery, and growth is completed merely in the beginning of adulthood. Different disorders of growth could possibly be witnessed, like a genuine duplication or multiplication of the sinuses with numerous isolated ostia or creation of septae forming many chambers in a single maxillary sinus. These kinds of variances commonly result in reduced mucociliary clearance from the maxillary sinuses and might trigger recurrent chronic sinusitis. Other paranasal sinuses start to develop prenatally as diverticles from the lateral nasal wall and slowly distinguish within the cranial bones (ethmoid, frontal, and sphenoid). These sinuses largely grow postnatally. The frontal and sphenoidal sinuses are not clinically noticeable at delivery, and their primary growth starts at about 2  years postnatally. The frontal sinuses may generally become recognized on X-ray at about 7 years of age. Additional growth of paranasal sinuses actually varies with time, and these sinuses may acquire their ultimate form and dimensions simply at the end of adolescence, providing the ultimate visual appeal to the face [9]. One can find four unique kinds of sinuses which will occur, though just two will be produced prior to birth. In the third gestational month, the maxillary sinuses, which are located within the maxillary bones, develop “as invaginations of the nasal sac that gradually enlarge in the maxillary bones.” They will be smaller at delivery; however, they will keep growing throughout the first couple of years. After 2 months, the ethmoid sinuses, placed in the middle of the eyes, will develop in the ethmoid bone and will keep on enlarging till adolescence. At beginning, the sinuses are so small that they are not noticed by radiographs, which makes the diagnosis of infections extra challenging [15]. In the first several ages following birth, the sphenoid and frontal sinuses can develop inside the bones of the identical name [4]. Interestingly, the growth of the sinus passage ways is one of the major determinants of the dimensions and appearance of the face. Their expansion throughout fetal growth and throughout adolescence may modify visual appeal and lead to the evolving of voice eventually in life [2]. Reports mapping the developmental sequence of the upper airways after birth have demonstrated that the

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d­ evelopment of the soft tissues identifying the upper airways, which includes the lymphatic system, retains its proportionality with the development of the skeleton of the face and therefore provides airway patency and stability all through the child years [9, 16].

3.3

Nasal Histology

The nose is the principal way in which air can be admitted into the airways and performs a respiratory and olfactory function. Considered from a respiratory perspective, the nose’s function is to condition air to allow a more efficient exchange of gas to occur within the lungs. Considered from an olfactory perspective, the nose can pick up numerous smiles and transfer information to the central nervous system for interpretation [17]. The vestibule of the nose and the surrounding skin resemble each other histologically. In the boundary of the nasal lining and the skin, a keratinized squamous epithelial surface gradually gives way to the epithelium of a cuboidal or columnar form, which in turn gives way to specialized respiratory epithelium, with cilia. This respiratory epithelium thereafter lines most of the inside of the nose and completely lines the paranasal sinuses. The only area of the nasal cavity not lined by respiratory epithelium is the roof [18]. The vestibular area within the nostrils has a lining of stratified squamous epithelium that is keratinized, in effect being continuous with the skin covering the outside of the nose (Fig.  3.1). Hairs within this area, termed vibrissae, catch particles of larger size floating in the air entering the nose. The limen nasi is the point at which this keratinized layer gives way to a columnar, pseudostratified epithelium

Fig. 3.1  The vestibule of the nasal septum and the surrounding skin, a keratinized squamous epithelial surface gradually gives way to epithelium of a cuboidal or columnar form. (HE × 100) (Courtesy of İsa Azgın)

Fig. 3.2  Nasal septal mucosa pseudostratified epithelium with cilia and containing goblet cells. (HE × 100) (Courtesy of İsa Azgın)

with cilia and containing goblet cells (i.e., respiratory epithelium) (Fig. 3.2). This epithelium envelops the base and walls both lateral and medial (up to slightly below the level of the superior conchae) of the nasal interior as far posteriorly as the choanae, which form the boundary of the inside of the nose posteriorly. Further, there are glands of a seromucous kind scattered throughout the mucosae, secretions which help to humidify inhaled air and entrap particle-sized foreign bodies from the air. The function of cilia is to move the entrapped foreign bodies towards the pharynx, from where they are either swallowed or expelled through the mouth [17]. There is a pseudostratified columnar epithelium lining the nasal vault surrounding the area of the ethmoidal cribriform plate, the superior portion of the concha, and the upper portion of the septum (overlying the vertical plate of the ethmoid). This olfactory epithelium is ciliated but has no goblet cells. There are a number of different cell lineages represented within the epithelium, which together work to achieve olfactory function. The turbinates are the bony portion of the conchae, which are overlain with mucosae. They function to direct air upward towards the olfactory epithelium. Bowman’s glands are located within the lamina propria. They produce a serous exudate in which odoriferous compounds are dissolved prior to coming into contact with the olfactory cilia (Bowman’s glands are also referred to as olfactory glands). Olfactory cilia resemble short hairs that pierce the mucosal lining and thereby encounter odoriferous molecules, stimulation by which produces nervous system impulses emanating from the olfactory neurons. Olfactory neurons have a bipolar morphology and span the width of the epithelium. An olfactory signal starts as stimulation to the olfactory cilia, resulting in electrical discharge that spreads along the axon of the olfactory neuron. The axon transits the ethmoidal crib-

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riform plate, thereby entering the cranial space and s­ ynapsing with olfactory bulb cells (mitral cells—forming the first cranial nerve) [17]. Where respiratory epithelium turning into olfactory epithelium can be seen with the naked eye by an alteration in color, respiratory epithelium is pinkish while olfactory epithelium is yellow. Microscopically, the constituent cells change, as does their morphology. There is in both cases a distinct demarcation. Olfactory epithelial cells, like those of the respiratory epithelium, are columnar, but they are typically taller than respiratory epithelial cells. Three other types of cell are found in olfactory epithelium: sustentacular cells (which have a support function and are dispersed through the entire epithelium), olfactory neurons, and basal cells. The outline of these different cell populations is of less use in distinguishing between them than the position and shape of the nuclei. Basal cell nuclei are spherical and are situated close to the cribriform plate, whereas sustentacular cells have nuclei which are long and thin and situated away from the cribriform plate. Olfactory neurons have nuclei which can be seen lying in between the basal and sustentacular cells. Respiratory epithelial mucosa is supplied with more blood vessels than olfactory mucosa. The nasal sinuses are lined with mucosae of respiratory epithelial type, which differs only in terms of having smaller epithelial thickness and smaller numbers of goblet cells and seromucous glands. Generally speaking, there is no lymphoid tissue found within the nasal sinuses [17]. Inflammation that occurs within the nasal mucosa is termed rhinitis. The underlying pathology may be viral or allergic. Excessive mucus secretion is revealed clinically as rhinorrhoea (watery discharge from the nose). Depending on the nature of the triggering allergens, allergic rhinitis may be persistent or restricted to a particular season. Inflammation confined within the mucosae of the paranasal sinuses is termed sinusitis. Typically, it is the result of bacterial overgrowth secondary to blockage of the ostium, which prevents the sinus draining properly [17].

References 1. Neskey D, Eloy JA, Casiano RR. Nasal, septal, and turbinate anatomy and embryology. Otolaryngol Clin North Am. 2009;42(2):193– 205. https://doi.org/10.1016/j.otc.2009.01.008. 2. Baylis A. Head and neck embryology: an overview of development, growth and defect in the human fetus. Honors Scholar Theses. Paper 105, 2009. http://digitalcommons.uconn.edu/srhonors_theses/105. Accessed 26 Aug 2015. 3. Nyberg DA, McGahan JP, Pretorius DH, Pilu G.  Diagnostic imaging of fetal anomalies. Philadelphia: Lippincott Williams & Wilkins; 2003. 4. Larsen WJ.  Human embryology. 2nd ed. New  York: Churchill Livingstone; 1997. 5. Moore KL, Persaud TVN. Before we are born essentials of embryology and birth defects. 4th ed. Philadelphia: Saunders; 1993. 6. Ferguson MW. Palate development. Development. 1988;103:41–60. 7. Nanci A.  Ten Cate’s oral histology development, structure, and function (Ten Cate's Oral Histology). 6th ed. St. Louis: Mosby; 2003. 8. Meng LZ, Torensma BR, Von den Hoff JW. Biological mechanisms in palatogenesis and cleft palate. J Dental Res. 2009;88:22–33. 9. Pohunek P. Development, structure and function of the upper airways. Paediat Respir Rev. 2004;5:2–8. 10. Djupesland PG, Lyholm B. Changes in nasal dimensions in infancy. Acta Otolaryngol. 1998;118:852–8. 11. Carlson BM.  Development of head and neck. In (eds): Human embryology and developmental biology. St Louis: Mosby, 1994. pp. 283-6. 12. Moore KL, Persaud TVN. The developing human. Clinically oriented embryology. Philadelphia: WB Saunders; 1998. 13. Bhatnagar KP, Smith TD, Winstead W.  The human vomeronasal organ: Part IV.  Incidence, topography, endoscopy, and ultrastructure of the nasopalatine recess, nasopalatine fossa, and vomeronasal organ. Am J Rhinol. 2002;16:343–50. 14. Bingham B, Wang RG, Hawke M, et al. The embryonic development of the lateral nasal wall from 8 to 24 weeks. Laryngoscope. 1991;101:992–7. 15. Rosin DF.  The sinus sourcebook. Los Angeles: Lowell House; 1998. 16. Arens R, McDonough JM, Corbin AM, et al. Linear dimensions of the upper airway structure during development. Am J Respir Crit Care Med. 2002;165:117–22. 17. No authors listed. Histology of the Upper Respiratory Tract. https:// www.kenhub.com/en/library/anatomy/histology-of-the-upperrespiratory-tract. Accessed 26 Aug 2015. 18. Walike JW. Anatomy of the nasal cavities. Otolaryngol Clin North Am. 1973;6:609–21.

4

Surgical Anatomy of the External and Internal Nose Engin Umut Sakarya, Murat Kar, and Sameer Ali Bafaqeeh

4.1

Introduction

Knowledge of surgical anatomy is critical to the success of septoplasty and rhinoplasty [1]. In particular, the anatomy of the nose and surrounding structures must be well known to surgeons [2]. The nose consists of three basic components: the nasal framework, the support, and the external cover. The nasal framework consists of the both cartilage and bones. The nasal support is generated through tissue and ligaments that hold the intrinsic framework together, while the skin and soft tissues form the nasal external cover [2]. In rhinoplasty operations, the main aims are: 1 . Precise definition of the abnormality/abnormalities 2. Adequate exposure of the nasal deformity 3. Conservation or reconstruction of the normal anatomy 4. Maintenance or restoration of the nasal airway.

4.2

Dermis

Dermal layer thickness is among the utmost essential elements in the preoperative assessment for rhinoplasty. The skin is generally thinner and looser in the superior portion of the nose and denser and stiffer caudally. Lessard and Daniel [3] reported that the thickest region was near the nasal front angle (1.25 mm) and the thinnest area was the rhinion (0.6  mm). The presence of sebaceous glands is

E. U. Sakarya (*) Otorhinolaryngology Department, Sada Hospital, İzmir, Turkey M. Kar Department of Otorhinolaryngology, Kumluca State Hospital, Antalya, Turkey S. A. Bafaqeeh Facial Plastic Division, Department of Otolaryngology, King Saud University, Riyadh, Saudi Arabia

more common in the inferior nasal area, leading to oily and dense dermal layer, which makes the tip more defined and difficult. Various changes in the nose that appear with age (i.e., tip drooping and nose lengthening) can result from alterations in the skin characteristics. The dermal layer is frequently thinner around the columella and alar rim, so the configuration of the lower lateral cartilage is apparent under the thin cover of the skin [1].

4.3

Subcutaneous Tissue

The subcutaneous tissue, a crucial concern in rhinoplasty, is located within the dermis and the osseocartilage [5]. This area was further divided into four distinct layers by Schlesinger et  al.: superficial panniculus, deep fatty layer, fibromuscular layer, and periosteum [5]. Open rhinoplasty surgery is accomplished under these regions. The blood source to the flap elevated in rhinoplasty allows for elevation in an avascular plane. Dissection within this level avoids damage to the subcutaneous tissues and minimizes scar tissue development [4].

4.4

Muscles

The muscles of the nose are comprised of four major sets: compressors, elevators, dilators, and depressors. These muscles interconnect with each other through the nasal SMAS (superficial musculoaponeurotic system) and are elevated in this S-STE flap in the course of open rhinoplasty [6, 7, 8, 9]. The depressor muscles elongate the nose during nostril dilation. The elevator muscles, on the other hand, shorten the nose during nostril dilation. Hyperactive depressor septi nasi muscles may lead to ptosis of the tip but could cause an undesirable look during smiling or laughing. The compressor muscles contribute to nasal elongation and nostril narrowing. Dissection in the appro-

© Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_4

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Fig. 4.1  Nasal muscles

Fig. 4.2  Blood supply

priate plane around these muscles reduces blood loss during surgery and maintenance of the soft tissues and protects the related blood supply, thus minimizing intraoperative hemorrhage, postoperative swelling, and scar tissue formation (Fig. 4.1) [4].

4.5

Blood Supply and Lymphatics

The nose contains a good blood supply, similar to the other parts of the face. The arteries of the nose primarily come from branches of [1] the ophthalmic artery of the internal carotid and [2] the external carotid arteries (Figs. 4.2, 4.3 and 4.4) [4]. The facial artery is found in the nose and intersects with the angular artery travelling superomedially around the nose. Branches that come from the internal maxillary artery and ophthalmic arteries supply the nose at the sellar and dorsal parts [1, 2, 4, 6]. Inside the nose, the sphenopalatine and the ethmoid arteries supply the nasal wall at the lateral side. The nasal septum receives its supply of blood from these arteries. The superior labial and the greater palatine arteries also contribute to its blood flow. The Kiesselbach’s plexus defines a region of the nasal septum in which all three of the primary arteries to the internal nasal area come together [6].

Fig. 4.3  Blood supply (lateral view)

The veins in the nasal area basically travel with the arteries, directly communicate with the cavernous sinus, and do not have valves, which increases the chance of intracranial spread of infection. Despite the rich nasal blood flow, smoking endangers postoperative healing in this area [6].

4  Surgical Anatomy of the External and Internal Nose

Fig. 4.4  Blood supply (basal view)

4.6

Nerves

Sensory innervation of the nasal area comes from the trigeminal nerve (Fig. 4.5) [4, 6]. Ophthalmic partition [6]: • Lacrimal—dermis of the lateral orbital region • Frontal—includes the supraorbital and supratrochlear skin regions • Nasociliary—includes the nasal cavity, anterior mucous membrane, and skin The nasociliary segment of the ophthalmic partition contains: • Anterior ethmoid • Posterior ethmoid • Infratrochlear nerve Maxillary partition [6]: • Maxillary • Infraorbital • Zygomatic • Superior posterior/anterior dental • Sphenopalatine

4.6.1 Parasympathetic Innervation The parasympathetic innervation comes from the seventh cranial nerve greater superficial petrosal (GSP) branch. The GSP connects to the deep petrosal nerve and carries the sym-

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Fig. 4.5  Sensory nerve supply of the external nose

pathetic innervation. The vidian nerve goes through the pterygopalatine ganglion and traverses the glands of the nasal mucosa and palate [6]. Injury to this nerve causes numbness of the tip that is generally observed following rhinoplasty since this division is susceptible in the course of intercartilaginous or cartilage-­ splitting openings. To reduce the risk of damage to this nerve, one should avoid planning deep endonasal incisions since the nerve is deep to the endonasal surface. Rather, the elevation could be kept atop the cartilage [4, 10]. Sensation to the soft tissues lateral to the inferior nasal portion is provided by infraorbital nerve of the maxillary division that innervates parts of the columella as well as the lateral vestibule [11].

4.7

Bony Vault and Septum

4.7.1 Bony Vault The bony vault defines the superior or cephalic nasal portion. The nasal bones connect superiorly to the frontal bones and laterally with the ascending maxilla process [4]. Superolaterally, these bones join the lacrimal bones (Figs. 4.6 and 4.7) [6]. The nasal bones display exceptional variation in their length and width [4]. However, they usually form a pyramid shape: broad at the nasofrontal angle, narrow at around the medial canthus, and turning out sideways inferiorly [12]. The nasal bones are thickest at the nasofrontal junction and become thinner as they widen inferolaterally [9]. Interestingly, nasal bone fractures are more common in the lower two-thirds of the nasal bones due to the thin bone structure [13].

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The nasal spine should be preserved in some form to maintain the correlation to the most anterior part of the quadrilateral cartilage and stabilize the nose during septal reconstruction [16]. The quadrilateral cartilage joins to the ethmoidal perpendicular plate posteriorly and sits in a groove that is formed by the maxilla inferiorly. Posteriorly, these structures articulate with the vomer (Fig. 4.9) [2]. The lateral walls of the nose contain three sets of small slim bones: the superior, middle, and inferior conchae. The medial maxillary sinus wall is found on the lateral side of the conchae. Below the conchae is an area termed the meatus. The ridge of the nose is comprised of the ethmoidal cribriform plate internally. Posteroinferiorly, the bony wall of the sphenoid sinus slopes down at an angle. Fig. 4.6  Frontal view of the nose

Fig. 4.7  Nasal bone and cartilages (lateral view)

The nasal bones create a characteristic depression at the supratarsal crease in Caucasians. Asian and African individuals possess a more inferiorly positioned radix. The nasal bone average length in Caucasians is 25 mm but can be much shorter in Asian and African individuals [14]. Alterations to this region shape the nose and the forehead.

4.7.2 Septum The bony part of the septum is comprised of the ethmoidal perpendicular plate posterosuperiorly. The vomer is placed posteroinferiorly and contributes to the formation of the choanal entrance into the nasopharynx. The premaxilla and the palatine bones form the floor of the bony septum (Fig. 4.8) [6].

4.7.2.1 Areas of the Nose In terms of diagnosis and documentation and to assist with correlating the pathology and symptomatology, Cottle (1961) [17] proposed to divide the nose into five areas internally: (1) the external ostium or naris, (2) the valve region, (3) the bony and cartilaginous vault region, (4) the anterior part, and (5) the dorsal part of the nasal cavity (Fig. 4.10) [18]. Although this classification is commonly recognized, it has become increasingly outdated, probably since Masing [19] and Ey [20] offered a different system. In their classification, areas 1, 2, 4, and 5 are the same as in Cottle’s, but they called the region of the premaxilla “area 3.” Huizing [18] recommends applying either the original Cottle’s classification to prevent any misconception or (possibly better) the anatomical nomenclature: nostril, vestibule, valve area, anterior nasal cavity, and posterior nasal cavity (the last two are categorized into the inferior, middle, and upper meatus). Physiologically, we favor partitioning the nose into three functional components: (1) anterior segment or adapter (upstream area), (2) middle segment or functional area, and (3) posterior segment (downstream area) [21].

4.8

Cartilaginous Pyramid

The cartilaginous septum has a quadrangular shape that descends from the middle nasal bones to the septal bone in the middle posteriorly and then caudally over the bony floor. Its superior one-half is in the middle of two upper lateral cartilages (ULCs), which bind to dorsal septa in the middle and connect to the pyriform aperture. The inferior edges of the ULCs are unrestricted. The internal angle that is produced by the upper lateral cartilage and septum forms the

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Fig. 4.8 Septum

Fig. 4.9  The nasal septum and its connections

internal valve. Adjoining sesamoid cartilages can be identified on the lateral sides of the ULCs in the fibroareolar connective tissue [6].

4.8.1 Upper Cartilaginous Vaults

Fig. 4.10  Areas of the nose according to Cottle: (1) the external ostium or naris, (2) the valve region, (3) the bony and cartilaginous vault region, (4) the anterior part, and (5) the dorsal part of the nasal cavity [18]

The upper cartilaginous framework, or midvault, consists of the paired ULCs and dorsal part of the septal cartilage. This framework starts at the “keystone” area, the place at which the nasal bones overlap the ULCs. Normally, this is the widest part of the dorsum and is similar to a “T” shape in cross section [15]. The ULCs extend under the nasal bones, and their junction forms a tight synchondrosis. These cartilages extend down to the scroll area, which has a variable anatomy and intersects the lower lateral cartilages (LLCs) and ULCs. The keystone area is shaped by the junction of the upper and lateral nose bones and dorsal septum. Internally, the junction

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a

b

Fig. 4.12  Alar cartilage

Fig. 4.11  Upper cartilaginous framework. (a) At the “keystone area,” nasal bones overlap the upper lateral cartilage. (b) At the “scroll area,” the lower lateral cartilages overlap the upper lateral cartilages [15]

forms a T-shaped structure. The dorsal contour of the nose is such that this area is the widest along the normal dorsum, which must be considered when reconstruction is required (Fig. 4.11) [2, 15].

4.8.2 Lower Cartilaginous Vault The lower cartilaginous framework consists of the medial, middle, and lateral crura and starts at the intersection of the LLCs and the ULCs, namely, the “scroll” area. The LLCs are connected to each other, the ULCs, and the septum by fibrous tissue and ligaments (Fig. 4.11). The disruption of these ligaments during rhinoplasty can result in diminished tip projection that requires reconstruction to maintain or increase tip support [15]. The LLCs are nearer to the longitudinal nose axis than usually visualized and do not encompass the nostril rim. The LLCs contain the medial crura that form the columella and turns into the slim intermediate crura at the nostril apex. Subsequently, it becomes the lateral crura, which strengthens the lower portion of the nose. The musculus levator labii

superioris alaeque nasi widens the nares and is connected to the LLC side. The columella consists of the nasal septum and medial crura of the LLC [22]. According to the conventional understanding of alar cartilage morphology, the medial and lateral crura are attached by an “anatomic” domal segment. Sheen and Sheen [23] offered the notion of the middle crus inferior edge at the columellar lobule junction and its superior edge at the junction of the lateral crus. Daniel’s studies place the domal portion in the very superior part of the middle crus [24], which is now called the intermediate crus [25]. Its complex and varying construction is so vital to the construction of the nasal lobule that it warrants distinct explanation and concern. In this session, each alar cartilage is separated into three components: the medial, middle, and lateral crura (Fig. 4.12) [1].

4.8.2.1 Medial Crus It contains two segments: the footplate and the columella. In most people, angulation happens within two planes: the cephalic rotation angle and the footplate divergence angle. The configuration of the medial crura that is formed by the angles has a notable effect on the shape and prominence of the flared part of the columellar base [1]. The columellar segment starts at the superior border of the footplate and completes at the junction of the columellar lobule (“columellar breakpoint”), where it is connected to the middle crus [1].

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4.8.2.2 Middle (Intermediate) Crus It consists of the lobular and domal sections. The lobular section varies widely in structure, although there is not much of a correlation between its particular internal structural configuration and the external form. Its superficial appearance is hidden by the thick skin and soft tissue [1]. 4.8.2.3 Lateral Crus The largest part of the nasal lobule greatly determines the form of the anterosuperior part of the alar wall. Medially, the lateral crus is continuous with the middle crus and is placed lateral to the accessory cartilages next to the pyriform process [26–28]. Caudally, its free border can be flat or curved backward at varying angles. The caudal border parallels and supports the anterior half of the alar rim [28, 29]. As it advances laterally, the caudal border curves superiorly from the alar rim. Hence, a bordering incision should not follow the alar rim except medially, at which point it can proceed cephalically to follow the border of the lateral crus [30]. The lower cartilaginous vault is supported as follows (Fig. 4.13) [2]: 1. Length and strength of the alar cartilages 2. Suspensory ligament

Fig. 4.14  The angle of the divergence

3. Fibrous connections between the lateral crura and the caudal edge of the ULCs 4. Abutment with the bony pyriform aperture 5. Anterior septal angle The angle of the divergence occurs at the middle crus of the lower lateral cartilages. It is important for determining the type of the tip, especially in a boxy or bifid tip (Fig. 4.14) [2].

4.9

Internal Nasal Anatomy

4.9.1 Turbinates

Fig. 4.13  Nasal tip support mechanisms

Three horizontal bones arising from the lateral wall are named as conchae. These bones are coated by fibrovascular erectile tissue to create the turbinates, which significantly decreases the volume of the nasal cavity yet expands the surface area exposed to air inflow. The turbinates enable warming, filtration, and humidification of the inspired air. The inferior turbinate is the largest and most readily recognized on anterior rhinoscopy. The middle turbinate is superior to the inferior turbinate and creates the medial wall of the ethmoid sinuses. The smaller superior turbinate, which is superior to the middle turbinate, is immediately under the cribriform plate [31]. The turbinates are mucosa-lined protrusions of the lateral nasal cavity that undergo cyclical enlargement and shrinkage controlled by the autonomic nervous system. Their function

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Fig. 4.15  Nasal valve

is to humidify and assist in the transport of air during respiration. The inferior turbinate, especially its anterior-­most portion, has the greatest impact on airway resistance, producing almost two-thirds of the resistance of the total airway [32]. Turbinate pathology is frequently addressed via submucosal resection and/or out fracture techniques. One must be careful, however, to avoid over-resection, because it can lead to adverse effects such as dysfunction of the regulatory and physiological pathways, crust formation, bleeding, and nasal cilia dysfunction [15].

caudal to the INV and is the vestibule that provides entry to the nose. This valve may be obstructed by external or internal factors such as foreign bodies or fragile LLCs, vestibular skin loss, or cicatricle tapering, respectively. There are many options to correct these potential problems, including but not limited to cartilage grafting, soft tissue grafting (mucosal, skin, or composite grafts), adhesional lysis, and scar revision [15].

4.9.2 Nasal Valve

References

The internal nasal valve (INV) is formed where the ULC joins the dorsal septum internally (Fig.  4.15). The angle between the ULC and dorsal septum is normally 10–15° to allow for the perception of unrestricted airflow [2]. The INV may be widened using flaring sutures [6]. The INV, which can produce almost one-half of the airway resistance, is the thinnest part of the nasal passage. Occasionally, the head (anterior-most portion) of the inferior turbinate can be hypertrophied enough to create further diminishing of the cross-sectional area of this region. Traditionally, a positive Cottle sign (lateral pull on the cheek leading to increased airflow) signals the collapse of the INV and indicates the need for flaring sutures to expand INV angle and open the airway [15]. The external nasal valve is

1. Oneal RM, Bell RJ Jr, Izenberg PH, Schlesinger J. Surgical Anatomy of the nose. Oper Tech Plast Reconstr Surg. 2000;7(4):158–67. 2. Kenyon G. Nasal anatomy and analysis. Otolaryngol Clin An Int J. 2013;5(1):34–42. 3. Lessard M, Daniel RK. Surgical anatomy of septorhinoplasty. Arch Otolaryngol Head Neck Surg. 1985;111:25–9. 4. Oneal RM, Beil RJ Jr, Schlesinger J. Surgical anatomy of the nose. Otolaryngol Clin N Am. 1999;32(1):145–81. 5. Steele NP, Thomas JR. Surgical Anatomy of the nose. In: Stucker FJ, de Souza C, Kenyon GS, Lian TS, Draf W, Schick B (Eds.). Rhinology and facial plastic surgery. Springer, Hardcover. ISBN: 978-3-540-74379-8. 2009, pp 5-12. http://www.springer.com/9783-540-74379-8. Accessed 9 June 2015. 6. Chang EW. Nasal anatomy. In: Meyers AD (ed) Medscape. http:// emedicine.medscape.com/article/835134-overview#showall. Accessed 9 June 2015. 7. Griesman BL.  The tip of the nose. Arch Otolaryngol Head Neck Surg. 1952;31(10):551–3.

4  Surgical Anatomy of the External and Internal Nose 8. Letourneau A, Daniel RK. Superficial musculoaponeurotic system of the nose. Plast Reconstr Surg. 1988;82(1):48–57. 9. Tardy ME.  Surgical anatomy of the nose. New  York, NY: Raven Press; 1990. 10. Firmin F. Discussion on Letourneau A, Daniel RK: The superficial musculoaponeurotic system of the nose. Plast Reconstr Surg 1988; 82:56–57. 11. Zide BM.  Nasal anatomy: the muscles and tip sensation. Aesthet Plast Surg. 1985;9:193–6. 12. Enlow DH. The human face: an account of post-nasal growth and development of the craniofacial skeleton. New York: Hober; 1968. 13. Rees TD. Aesthetic plastic surgery. Philadelphia PA: WB Saunders; 1980. 14. Zingaro EA, Falces E.  Aesthetic anatomy of the non-Caucasian nose. Clin Plast Surg. 1987;14(4):749–65. 15. Jones NS. Principles for correcting the septum in septorhinoplasty: two-point fixation. J Laryngol Otol. 1999;113(5):405–12. 16. Cottle MH.  Personal communication. 2nd Int. course in septum-­ pyramid surgery, Jerusalem, 1961. 17. Huizing EH. Incorrect terminology in nasal anatomy and surgery, suggestions for improvement. Rhinology. 2003;41:129–33. 18. Masing H. Eingriffe an der Nasenscheidewand. In: Naumann HH (ed) Kopf- und Hals Chirurgie. Thieme, Stuttgart, 1974. 19. Ey W. In: Denecke HJ, Ey W, editors. Die Operationen an der Nase und im Nasopharynx. Berlin: Springer; 1984. 20. Huizing EH, de Groot JAM.  Functional reconstructive nasal surgery. Stuttgart: Thieme; 2003.

47 21. Janis JE, Rohrich RJ.  Rhinoplasty. In: Thorne CH (ed.) Grabb and Smith’s plastic surgery. Chapter 51. Sixth edition. Lippincott Williams & Wilkins, a Wolters Kluwer Business; 2007, pp. 517–32. 22. Jones N. The nose and paranasal sinuses physiology and anatomy. Adv Drug Deliv Rev. 2001;51:5–19. 23. Sheen JH, Sheen AP. Aesthetic rhinoplasty. 2nd ed. St. Louis: MO, Mosby; 1987. 24. Daniel RK. The nasal tip: Anatomy and aesthetics. Plast Reconstr Surg. 1992;89:216–24. 25. Tardy ME, Brown RJ.  Surgical anatomy of the nose. New  York: Raven; 1990. 26. Jost G, Meresse B, Torossian F. Studies of junction between lateral cartilages of the nose. Ann Chir Plast. 1973;18:175–82. 27. Daniel RK, Letourneau A. Rhinoplasty: nasal anatomy. Ann Plast Surg. 1988;20:5–13. 28. Dion MD, Jefek BW, Tobin CE.  The anatomy of the nose. Arch Otolaryngol. 1978;104:145–50. 29. Gunter JP. Anatomical observations of the lower lateral cartilages. Arch Otolaryngol. 1969;89:599–601. 30. Bernstein L. Surgical anatomy in rhinoplasty. Otolaryngol Clin N Am. 1975;8:549–58. 31. Cheesman K, Burdett E.  Anatomy of the nose and pharynx. Anaesthesia and Intensive Care Medicine. 2011;12(7):283–6. 32. Rohrich RJ, Krueger JK, Adams WP Jr, Marple BF. Rationale for submucous resection of hypertrophied inferior turbinates in rhinoplasty: an evolution. Plast Reconstr Surg. 2001;108(2):536–44; discussion 545-6.

5

Surgical Anatomy of the Paranasal Sinuses Yeşim Başal, Sema Başak, and Jeffrey C. Bedrosian

5.1

Introduction

The paranasal sinuses are air-filled cavities, located inside the bones of the skull, with their ostia opening into the nasal cavity. The maxillary, ethmoid, sphenoid and frontal sinus, ethmoid sinus, and sphenoid sinus are named after the bone in which they are located [1]. The anatomy of the paranasal sinuses is quite complex and prone to individual variation; however, basic surgical anatomy should be understood in order to avoid complications. This chapter aims to present the anatomy of paranasal sinuses, emphasizing their surgical anatomic characteristics.

5.2

The Maxillary Sinus

The maxillary sinus is the largest paranasal sinus. In adults, the maxillary sinus is a pyramidal cavity, with a length of 22 mm, height of 33 mm, and depth of 34 mm, having an average volume of 15 ml [2]. It is bounded by the maxillary surface anteriorly, the orbital floor superiorly, the hard palate and the alveolar ridge inferiorly, the zygomatic process laterally, and the outer lateral wall of the nasal cavity medially. It is separated from the infratemporal fossa and the pterygopalatine fossa by a thin bony layer posteriorly. The anterior wall thickness of the maxillary sinus varies between 2 and 5 mm. While the floor of the maxillary sinus is at or above the level of the nasal floor in children, it is approximately 5–10 mm lower in adults [3]. The bone-free part of the medial wall of the maxillary sinus is a membranous fontanelle consisting of mucosa and connective tissue [3]. While the natural ostium of the

Y. Başal (*) · S. Başak Department of Otorhinolaryngology, Medical Faculty, Adnan Menderes University, Aydın, Turkey J. C. Bedrosian Rhinology and Skull Base Surgery, Specialty Physician Associates, St. Luke’s Medical Centre, Bethlehem, PA, USA

maxillary sinus is located at the anterior part of membranous fontanelle, an accessory ostium may be present with a rate of 20–25% in the posterior part (Fig. 5.1). The size of the accessory ostium varies between 1 and 10  mm. Following an incomplete uncinectomy, the accessory ostium may be confused with the natural ostium [4]; however, when its round shape and posterior fontanelle location is considered, the accessory ostium can be easily differentiated from the natural ostium. The natural ostium of the maxillary sinus opens into the ethmoidal infundibulum. The ethmoidal infundibulum is a funnel-shaped, three-dimensional space that comprises a part of the osteomeatal complex. It is bordered by the uncinate process medially, the lamina papyracea laterally, the maxillary frontal process anterosuperiorly, and the lacrimal bone superolaterally. The anterior wall of the ethmoidal bulla constitutes the posterior border of the ethmoidal infundibulum. To reach the ethmoidal infundibulum via the nasal passage, one must pass through a two-dimensional plane named the hiatus semilunaris. The hiatus semilunaris is a crescent-shaped interspace, located between the free edge of the uncinate process and the anterior wall of the ethmoidal bulla. The natural ostium of the maxillary sinus opens into the anterior one-third part of the ethmoidal infundibulum with a rate of 5.5%, into the middle one-third part of the ethmoidal infundibulum with a rate of 11%, and into the posteroinferior part of the ethmoidal infundibulum with a rate of 72% [5]. The natural ostium can be reached by elevating the uncinate process, which constitutes the inner lateral wall of the ethmoidal infundibulum, during endoscopic surgery. The canine fossa is present in the anterior wall of the maxillary sinus, between the infraorbital foramen and the alveolar process. The anterior superior alveolar artery and nerve course inside the bony wall between the canine fossa and the maxillary sinus. The thickness of the bony wall decreases down to 1 mm at the deepest part of the canine fossa. The relationship between the maxillary sinus and the teeth may vary depending on the degree of pneumatization. While the maxillary third molar tooth is closest to the floor, the canine tooth or

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Fig. 5.1  Accessory ostium of maxillary sinus Fig. 5.2  Maxillary sinus hypoplasia

the first and second molar teeth rarely reach the floor of the sinus. Dehiscence of a tooth root into the maxillary sinus may result in an oroantral fistula. Some variations of the maxillary sinus should be considered prior to surgery. A Haller cell is the most frequently met anatomical variation. This infraorbital ethmoid cell is located between the orbital floor and the roof of the maxillary sinus, below the ethmoidal bulla, and lateral to the uncinate process. Haller cells originate from anterior ethmoidal cells with a rate of 88% and posterior ethmoidal cells with a rate of 12% [6]. The dimensions of a Haller cell vary widely. Sometimes, it can display such an extensive pneumatization that it may lead to the appearance of a “second maxillary sinus.” A large Haller cell may obstruct the natural ostium of the maxillary sinus, leading to rhinosinusitis. Additionally, Haller cells can create some difficulty when identifying the maxillary sinus natural ostium during endoscopic sinus surgery. Other anatomic variations of the maxillary sinus include maxillary hypoplasia and atelectasis [7, 8] (Fig.  5.2). Maxillary sinus hypoplasia or atelectasis may be interpreted as sinus opacity radiologically. Since the maxillary sinus and the uncinate process develop from the cartilaginous nasal capsule, their anomalies frequently occur together [9]. Maxillary sinus hypoplasia and aplasia are commonly accompanied by the anomalies of the uncinate process and the ethmoidal infundibulum. Therefore, it is important to know these variations before endoscopic surgery to avoid complications. Variations such as the lateralization, hypoplasia, aplasia of the uncinate process, atelectasis of the ethmoidal infundibulum, and lateralization of the membranous fontanelle into the sinus may be present [10]. In such situations, the uncinate process might not be able to be identified, and orbital complications can develop during middle meatal antrostomy [7, 11] (Figs. 5.3 and 5.4). The maxillary sinus

Fig. 5.3  Bulging of inferomedial orbital rim to nasal cavity and maxillary sinus hypoplasia

may contain partial septations that can block the sinus drainage. Among these, the most frequently seen are located at the anterosuperomedial part [12]. The septations are mostly incomplete; however, rarely, these septae reach sizes that can completely separate the sinus into two. The maxillary sinus arteries are the anterosuperior and the posterosuperior branches of the greater palatine artery branch of the maxillary artery. Its venous drainage occurs via the anterior facial vein into the jugular vein and the pterygoid venous plexus. Its lymphatic drainage is into the submandibular lymph nodes. Its sensorial innervation is via the greater palatine and infraorbital branches of the maxillary nerve [1].

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adhere to the lamina papyracea, the skull base, or the middle concha [13]. It is important to pay attention to the insertion point in order to avoid complications that may develop during surgery. Utmost attention should be paid particularly when the uncinate process inserts superiorly onto the skull base (Fig.  5.5). Additionally, in cases of maxillary sinus hypoplasia, uncinated atelectasis may closely contour the inferomedial wall of the orbit and may provide a basis for orbital complications.

5.3.1.2 Bulla Ethmoidalis The ethmoid bulla is the largest anterior ethmoid sinus and has the least variability regarding location among all ethmoid sinuses (Fig.  5.6). The ethmoid bulla is the frontmost anterior ethmoidal cell, adjacent to the middle

Fig. 5.4  Endoscopic image of the same patient

5.3

Ethmoid Sinuses

The ethmoid sinus is considered a labyrinthine structure, due to its complexity and individual variations. It consists of 3–18 cells, having a honeycomb appearance. The anteroposterior distance is 4–5 cm and it has a height of 2–3 cm, while its width is 0.5 cm anteriorly and 1.5 cm posteriorly and its volume is 14 ml on average. The ethmoidal labyrinth consists of obliquely oriented, parallel lamellae. The first lamella is the uncinate process, the second is the ethmoid bulla, and the third lamella is the basal lamella of the middle concha. The basal lamella is a key surgical landmark as it separates the anterior and posterior ethmoidal cells from each other. Conservation of this lamellar structure from person to person makes it helpful during surgery [11]. Anterior and posterior ethmoid cells are also differentiated from each other by the drainage site of their ostia.

Fig. 5.5  Uncinate process adheres to the skull base

5.3.1 Anterior Ethmoid Sinus The ostia of the anterior ethmoid cells open into the middle meatus. This region involves some surgically significant cells, processes, and spaces.

5.3.1.1 Uncinate Process The uncinate process is a sickle-shaped bone, with a very tiny structure. It has a width of 3–4  mm and a length of 1.5–2 cm. This bone inserts on the lateral nasal wall anterosuperiorly and to the inferior concha posteroinferiorly. There is large variation of the insertion point on the superior part of the uncinate. Stammberger described these variations, stating that the uncinate process might terminate freely or might

Fig. 5.6  Ethmoid bulla and posterior wall of ethmoid bulla

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meatus. This cell is located posterior to the uncinate process, lateral to the lamina papyracea, and anterior to the basal lamella of the middle concha. It may manifest various degrees of pneumatization. An extensively pneumatized ethmoid bulla may contribute to rhinosinusitis. In situations in which it is not pneumatized, it is replaced by a bony process named the torus lateralis, originated from the lamina papyracea. The natural ostium of the ethmoid bulla is usually located posteromedially, within the retrobullar recess.

5.3.1.3 Retrobullar and Suprabullar Recesses The retrobullar recess or the sinus lateralis is the space immediately posterior to the ethmoid bulla and anterior to the basal lamella. It is bordered by the fovea ethmoidalis superiorly, the lamina papyracea anterolaterally, and the roof of the ethmoid bulla inferiorly [13]. If the ethmoid bulla does not extend to the skull base, the retrobullar recess will be contiguous with the suprabullar recess. The suprabullar recess is located between the lamina papyracea laterally, the roof of the ethmoid bulla inferiorly, and the skull base superiorly. The basal lamella of the middle concha constitutes the posterior border. If the lamella of ethmoid bulla does not extend to the skull base, the suprabullar recess opens into the frontal recess. These recesses can be reached superiorly from the hiatus semilunaris. 5.3.1.4 Ostiomeatal Unit The ostiomeatal unit is a space that plays a significant role in the etiology of rhinosinusitis. It is the last common pathway of the maxillary, frontal, and anterior ethmoid sinuses. It is the functional space between the lateral nasal wall, the ethmoid bulla, and the middle concha [14]. One of the major complications that can occur during endoscopic sinus surgery is the injury to the anterior skull base. Keros defined the depth of the lamina cribrosa in three categories [15]. The depth is 1–3  mm in Keros type I, 4–7 mm in Keros type II, and 8–16 mm in Keros type III. As the lamina cribrosa gets deeper, the lateral lamella gets thinner, and the ethmoidal roof is displaced onto the cribriform plate [11, 13]. Skull base injury along the lateral lamella is most likely to occur in Keros type III anatomy. The existence of an asymmetry between the two sides should be investigated during the assessment of the computerized tomographic images preoperatively. The anterior ethmoidal artery enters the nasal cavity through the foramen at the frontoethmoidal suture line (Fig. 5.7). The thickness at the site that the artery emerges from the skull base is 0.5 mm at the ethmoid bone side and may be violated during endoscopic sinus surgery; cerebrospinal fluid leakage is encountered most frequently in this

Fig. 5.7  Anterior ethmoidal artery

site [16]. The artery courses inside canalis ethmoidalis anterior within the nasal cavity. This canal can course along the skull base, or it might run freely in a mesentery between the ethmoidal cells. The free course of the artery can provide a basis for the development of complications. The entrance of the artery into the orbit is through the anterior ethmoidal foramen, located 18 mm posterior to the lacrimal crest (frontomaxillolacrimal suture). This foramen can be identified as a “V”-shaped protrusion on CT—an important landmark for identifying the free course of the artery or its course along the skull base [17].

5.3.2 Posterior Ethmoid Sinuses The posterior ethmoid sinus consists of one to five cells. It is bordered by the basal lamella of the middle concha anteriorly; the anterior wall of the sphenoid sinus posteriorly; the lamina papyracea laterally; the superior concha, the vertical part of the concha suprema, and the associated meatuses medially; and the ethmoidal roof superiorly [11]. Its dimensions may vary over a wide range. The posterior ethmoidal cells may extend posterolaterally or posterosuperiorly, and it may lie directly adjacent to the optic nerve (Onodi cell) (Fig. 5.8). If an Onodi cell is present during surgery, the risk of optic nerve-related complications is high. The apex of the posterior-most ethmoid cell can always be observed as a posterosuperolaterally localized pyramid-shaped structure; therefore, it can be used as a reliable landmark during surgery. The posterior ethmoidal artery, after exiting the skull base, courses within the nasal passage and enters the orbit through the posterior ethmoidal foramen, located 12  mm posterior to the anterior ethmoidal foramen. The distance of this foramen to the optic nerve is 6 mm.

5  Surgical Anatomy of the Paranasal Sinuses

Fig. 5.8  Onodi cell

5.4

Sphenoid Sinus

The sphenoid sinus is located in the corpus of the sphenoid bone, located at the center of the skull base. The right and left sphenoid sinuses are separated from each other by the intersinus septum. Its vertical diameter is 20 mm, its transverse diameter is 18  mm, its anteroposterior diameter is 21 mm, and its volume is approximately 7.5 ml. The pituitary gland, the optic nerve, and the optic chiasm are located posterosuperiorly to the sphenoid sinus. The carotid artery, the optic nerve, the cavernous sinus, and third, fourth, fifth, sixth cranial nerves are present lateral to the sphenoid sinus [18]. If the sphenoid sinus is extensively pneumatized, the optic nerve and the carotid artery may extend into the sinus. Dehiscence of these structures is observed in some situations. The dehiscence rate of the carotid canal was reported to be 22.8% unilaterally and 7.6% bilaterally [19]. The anterior edge of the sphenoid sinus is adjacent to the posterior wall of the orbit. The floor of the sphenoid sinus constitutes the roof of the nasopharynx. The nerve of the pterygoid canal passes through the bony wall at the floor of the sphenoid sinus. The sphenoid sinus is separated from the pons and the basilar artery by the clivus. Onodi cells may pneumatize superiorly and laterally to the sphenoid sinus as a pyramid-shaped structure. Therefore, the presence and degree of pneumatization are important in sphenoid sinus surgery. The sphenoid sinus drains into the sphenoethmoid recess by a single ostium. This ostium is 2 × 3 mm in size, and since it is 1 cm above the floor of the sinus, mucociliary activity is

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required for the drainage of the sinus [20]. The natural ostium was reported to be located at the upper one-third part at a rate of 52% and at the middle one-third part at a rate of 34% [20]. The sphenoid ostium drains medially to the superior concha with a frequency of 83% and laterally with a frequency of 17% [21]. The ostium of the sphenoid sinus is 7 cm from the columella, when viewed from the base of the nose with a 30o angle to the parasagittal plane. It is located 10–12 mm superior to the upper limit of choana, 5 mm lateral to the nasal septum, and 1–1.5  cm superior to the sinus floor [22]. The carotid artery is located inferolateral to the ostium with 45o angle and a distance of approximately 25 mm. The optic canal is located superolateral to the ostium with 60o angle and a distance of 15 mm [23]. The upper wall of the sphenoid sinus constitutes the floor of the sella turcica, and the pneumatization of the sphenoid sinus is classified in three forms. In the conchal type, pneumatization is not present. In the presellar type, the sphenoid sinus shows pneumatization toward the frontal plane of the sella. The sellar type is the most common type, in which the sphenoid sinus is extensively pneumatized and the floor of the sella is located within the sinus [24]. The variations of the sphenoid sinus should be taken into consideration during surgery. The existence of numerous variations can be detected by a detailed evaluation of CT. The relationship of the sinus with the carotid artery and the optic nerve should be evaluated. The protrusion of these structures into the sinus and the possible bony dehiscence should be noted. Importantly, the bony canal of one carotid artery may be contiguous with the intersphenoid sinus septum. Inadvertent septal fracture in these cases places the artery at risk of rupture. [17] (Fig. 5.9).

Fig. 5.9  Dangerous intersphenoid septum

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5.5

Frontal Sinus

The frontal sinus has close embryological and anatomic relationship with the ethmoid sinuses. The right and left frontal sinuses develop independently of one another, and they are frequently asymmetrical. Dominancy, hypoplasia, aplasia, or extensive pneumatization may be identified. Every frontal sinus cavity is pyramid-shaped. The anterior wall of the frontal recess is formed by the thick bone of the frontal process of the maxilla. It starts from the nasofrontal suture line and is also called the beak of the frontal process [25]. The dimensions of this process vary depending on the pneumatization of the agger nasi cells—the anterior-most ethmoid cells. In the presence of less pneumatized agger nasi cell, the frontal process extends significantly toward the recess and the frontal ostium is narrowed. In adults, the frontal sinus has a height of 3 cm, a width of 2.5 cm, and a depth of 1.9 cm, on average. Its interior volume is 10 ml; however, it may sometimes reach 37 ml. The frontal sinus is divided into partitions by incomplete septae [26]. The height of the frontal sinus cavity varies between 1 and 6 cm, depending on the degree of pneumatization. The cortical bone thickness of the anterior wall is between 4 and 12 mm, and it is covered by pericranium, the frontal muscle layer, subcutaneous fat tissue, and the skin. The pericranial layer is used in the repair of anterior skull base defects and for the obliteration of the frontal sinus. The posterior wall of the frontal sinus is formed by the upward continuation of the anterior face of the ethmoid bulla. When the anterior wall of bulla cannot reach the skull base, the suprabullar recess continues as the frontal recess. The frontal sinus opens into the frontal recess or the anterior part of the infundibulum. The frontal recess is hourglassshaped. It is neighbored by the uncinate process and any agger nasi anteriorly, the ethmoid bulla and the suprabullar lamella posteriorly, the lamina papyracea laterally, the hiatus semilunaris and the middle concha medially, the ethmoid infundibulum inferiorly, and the fovea ethmoidalis, supraorbital cells, the anterior ethmoidal artery, and the frontal ostium superiorly [27]. The ostium of the frontal sinus is located at the posteromedial part of the sinus floor. The sinus drains either through the nasofrontal duct or directly into the infundibulum. The ostium of the frontal sinus is located along the coronal plane of the natural ostium of the maxillary sinus, a few millimeters posterior to the attachment site of the middle concha, and parallel to the convexity of the lacrimal bone [28]. The safe method for opening the frontal sinus is to open the agger nasi cell and to find the ostium anteriorly to the anterior ethmoidal artery. The fovea ethmoidalis constitutes the roof of the frontal recess. This bone is thick and resistant to penetration. The right fovea ethmoidalis is located higher than the left one with a frequency of 59% [29].

5.5.1 Agger Nasi Cell Agger nasi cells are most commonly seen nasofrontal cells. They are found with an incidence of more than 90% in cadaver dissections [30]. However, their recognizability on CT is lower. Preoperative understanding of the relationship between the agger nasi cell and the uncinate process is necessary. The uncinate process or the medial wall of the agger nasi cell may adhere to the lamina papyracea (Fig. 5.10). In most of these patients, the upper extension of the adherence site reveals a bony layer which divides the frontal recess vertically. The frontal sinus drains medial to this bony layer [25]. In the presence of a large agger nasi cell, the upward extension of the uncinate process is pushed medially and the uncinate process adheres to the middle concha. Thus, the drainage pathway of the frontal sinus is pushed posteriorly and the surgeon cannot reach the frontal sinus from the medial aspect of the uncinate process. The presence of frontal cell variations can affect the drainage of the frontal sinus [31]. The classification suggested by Kuhn concerning the cells located in the frontal region is shown in Table 5.1. The arteries of the frontal sinus stem from the supraorbital and supratrochlear branches of the ophthalmic artery. Venous drainage is into the cavernous sinus, via the ophthalmic vein. Lymphatic drainage is into the submandibular lymph nodes. Their innervation is by the supraorbital and supratrochlear branches of the ophthalmic nerve [32].

Fig. 5.10  Agger nasi cell Table 5.1  The classification of the frontal cells Type 1 Type 2 Type 3 Type 4

Single cell of the AN cell Cluster of cells on the AN cell Single cell extending from the AN cell to the frontal sinus, pneumatizing the lumen Isolated cell within the frontal sinus, covering entire space

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5.6

Conclusion

The anatomy of the paranasal sinuses is complex and variable. Particularly, the anatomy of the ethmoid sinus varies from person to person. A sound surgical anatomy and intimate acquaintance with potential variations that may be encountered are of great importance for the prevention of complications in endoscopic sinus surgery.

References 1. Çakır N.  Otolaryngology head and neck surgery. Istanbul: Nobel Medical Bookstores; 1999. 2. Arıkan OK. Anatomy and physiology of the paranasal sinuses. In: Koç C, editor. Otolaryngology and head and neck surgery. Ankara: Güneş Bookstores; 2004. 3. Van Cauwenberge P, Sys L, De Belder T, et al. Anatomy and physiology of the nose and the paranasal sinuses. Immunol Allergy Clin N Am. 2004;24:1–17. 4. Sargi ZB, Casiano RR. Surgical anatomy of the paranasal sinuses. In: Kountakis SE, Önerci M, editors. Rhinologic and sleep apnea surgical techniques. Heidelberg: Springer; 2007. 5. Van Alyae OE.  Ostium maxillare: anatomic study of its surgical accessibility. Arch Otolaryngol Head Neck Surg. 1936;24:552–69. 6. Kainz J, Braun H, Genser P.  Haller's cells: morphologic evaluation and clinico-surgical relevance. Laryngorhinootologie. 1993;72:599–604. 7. Bolger WE, Woodruff WW Jr, Morehead J, et  al. Maxillary sinus hypoplasia: classification and description of associated uncinate process hypoplasia. Otolaryngol Head Neck Surg. 1990;103:759–65. 8. Bolger WE, Kennedy DW.  Atelectasis of the maxillary sinus. J Respir Dis. 1992;13:1448–50. 9. Wang RG, Jiang SC, Gu R.  The cartilaginous nasal capsule and embryonic development of human paranasal sinuses. J Otolaryngol. 1994;23:239–43. 10. Wood S, Sinus M. In: Youngs R, Evans K, Watson M, editors. The paranasal sinuses. London: Taylor & Francis; 2006. 11. Bolger E.  Anatomy of the paranasal sinuses. In: Kennedy DW, Bolger WE, Zinreich SJ, editors. Sinus diseases. Istanbul: Nobel Medical Bookstores; 2003. 12. Karmody CS, Carter B, Vincent ME.  Developmental anatomy of the maxillary sinus. Trans Am Acad Ophthalmol Otolaryngol. 1997;84:723–80. 13. Stammberger H.  Functional endoscopic sinus surgery: the Messerklinger technique. Philadelphia: BC Decker; 1991.

55 14. Nauman H.  Patholische anatomic der chronischen rhinitis und sinisitis. In: Proceedings VIII International Congress of Otorhinolaryngology, Amsterdam, 1965. Excerpta Medica, p 12. 15. Keros S. Uber die praktische beteudung der Niveau-Unterschiede der lamina cribrosa des ethmoids. In: Nauman HH, editor. Head and neck surgery. Philadelphia: WB Saunders; 1980. 16. Kainz J, Stammberger H. The roof of the anterior ethmoid: a place of least resistance in the skull base. Am J Rhinol. 1989;3:191–9. 17. Basak S, Karaman CZ, Akdilli A, et al. Evaluation of some important anatomical variations and dangerous areas of the paranasal sinuses by CT for safer endonasal surgery. Rhinology. 1998;36:162–7. 18. Wyllie JW, Kern EB, Djalilian M. Isolated sphenoid sinusitis of the nose. Bailliere. London: Tindalland Cox; 1910. 19. Sirikci A, Bayazit YA, Bayram M, et al. Variations of sphenoid and related structures. Eur Radiol. 2000;10:844–8. 20. Kim HU, Kim SS, Kang SS, et al. Surgical anatomy of the natural ostium of the sphenoid sinus. Laryngoscope. 2001;111:1599–602. 21. Lang J, Bressel S, Pahnke J. The sphenoid sinus, clinical anatomy of approaches to the pituitary region. Gegenbaurs Morphol Jahrb. 1988;134:291–307. 22. Dixon FN. A comparative study of the sphenoid sinus (a study of 1600 skulls). Ann Otol Rhinol Laryngol. 1937;46:687–98. 23. Enatsu K, Takasaki K, Kase K, et al. Surgical anatomy of the sphenoid sinus on the CT using multiplanar reconstruction technique. Otolaryngol Head Neck Surg. 2008;138:182–6. 24. Sethi DS, Stanley RE, Pillay PK. Endoscopic anatomy of the sphenoid sinus and Sella turcica. J Laryngol Otol. 1995;109:951–5. 25. Wormald PJ.  Endoscopic Sinus surgery, anatomy, three-dimen sional reconstruction, and surgical technique. New  York: Thieme Medical Publishers; 2009. 26. Skinner D, White P. Anterior ethmoid sinus and frontal sinus. In: Youngs R, Evans K, Watson M, editors. The paranasal sinuses. London: Taylor & Francis; 2006. 27. Stammberger HR, Bolger WE, Clement PAR, et al. Anatomic terminology and nomenculature in sinusitis. Ann Otol Rhinol Laryngol Supp. 1995;104:7–19. 28. Casiano RR. A stepwise surgical technique using the medial orbital floor as the key landmark in performing endoscopic sinus surgery. Laryngoscope. 2001;111(6):964–74. 29. Floreani SR, Nair SB, Switajewski MC, et  al. Endoscopic anterior ethmoidal artery ligation: a cadaver study. Laryngoscope. 2006;116:1263–7. 30. Bolger WE, Butzin CA, Parsons DS. Paranasal sinus bony anatomic variations and mucosal abnormalities: CT analysis for endoscopic sinus surgery. Laryngoscope. 1991;101(1. Pt 1):56–64. 31. Bent JP, Cuilty-Siller C, Kuhn FA. The frontal cell as a cause of frontal cell obstruction. Am J Rhinol. 1994;8:185–91. 32. Kuhn FA.  Surgery of the frontal sinus in disease of the sinuses; diagnosis and management. In: Kennedy DW, editor. Diseases of the sinuses. London: BC Decker; 2001.

6

Physiology of the Nose and Paranasal Sinuses Mehmet Emre Dinç, Nuray Bayar Muluk, and Becky M. Vonakis

6.1

Introduction

The nasal area filters out particles and humidifies the air that goes to the lungs. It also acts as first-line immunological protection enabling the exposure of the inspired air to the mucosal membranes that hold immunoglobulin A (IgA). Breathing in through the nose, the air travels cranially in the nasal area and interacts with the olfactory nerves, which produces the smell sensation that is very well related to the sense of taste. A problem in association with this system can result in nasal symptoms such as postnasal drainage, headaches, facial pressure, congestion, and sinus infections [1].

6.2

Nasal and Sinus Mucosa

The mucosa of the respiratory system consists of pseudostratified epithelium with hair cells, along with muciparous, strial, and basal cells. Hair cells are the most differentiated cells of the nasal mucosa [2, 3]. The ciliated columnar epithelial mucosa that lines the nasal area and paranasal sinuses continues with the squamous epithelium of the anterior nasal cavity and pharynx, respectively. Ciliated epithelium occupies a more significant portion of the anterior nasal area in the newborn and laryngectomized individuals compared to others indicating the squamous metaplasia of ciliated epithelium, which develops as a reaction to the trauma of environmental exposures. The area of the luminal

surface of the columnar epithelium lining the rest of the sinonasal area is significantly widened by 200–300 microvilli/ cell, which potentiate the chance of transport between nasal cavity and epithelium. A great majority of the columnar cells have cilia as well, numbering 100/cell, beating 1000/min along with the nearby ciliated cells. The mechanisms behind this organized metachronous task remain to be explained [4]. Normally, the cilia beat in a serous periciliary fluid of low viscosity. The fluid is deep so that it prevents the entanglement of cilia with the discontinuous islands of viscoelastic mucus floating on its surface. However, it is not deep enough to avoid the tips of the beating cilia that push mucous through the pharyngeal pathways, which is then sent to oesophagus (Fig.  6.1) [5, 6]. The floating masses of mucous carry the entrapped and dissolved pollutants from the surrounding inhaled air, and through their route to the pharynx, they clean the cellular debris, microorganisms, and other detritus from the serous surface [5]. Mucociliary function is extremely resistant to extreme climates, to modest amounts of most of the air pollutants in the environment (including cigarette smoke), to particulate loading, to diverse variances in pH, and to most of the prescribed nasal medicines [5].

M. E. Dinç (*) Department of Otorhinolaryngology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey N. Bayar Muluk Department of Otorhinolaryngology, Medical Faculty, Kırıkkale University, Kırıkkale, Turkey B. M. Vonakis Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA e-mail: [email protected]

Fig. 6.1  Mucociliary transport

© Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_6

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The cytoplasm of the cilia consists of distinctly designed ultrastructural components which produce the flexion and extension of ciliary beating [7]. Anomalies regarding these ultrastructures can lead to dyskinesias that are inherited as primary disorders (Kartagener’s, Young’s, and other less distinctly described autosomal recessive inherited syndromes). Ciliary diseases are not restricted to the nose; in fact, they are greatly dispersed and can also be seen in the peripheral respiratory system as well as in other cells that possess cilia. Likewise, anomalies of the ciliary bodies accompany mucosal injury (from infections and different types of irritation), and they include cytoplasmic extrusions in the form of blebs and outgrowths of the ciliary membrane [5]. Hair cells and muciparous cells are the primary level of defence of the upper respiratory tract (mucociliary system). They exist in the mucosa in a ratio of 5 to 1. In the normal mucosa, nothing but scarce neutrophils is seen besides these cells. The occurrence of eosinophils, mast cells, bacteria, and/or fungal hyphae or spores in the nasal mucosa is an indication of nasal pathology [8]. Disorders of the nose have an effect on hair cells and establish mucosal remodelling by increasing the amount of muciparous cells (muciparous metaplasia). This remodelling results in elevation in the generation of mucous, and diminishment in hair cells at the same time which hinders the mucociliary transport (TMC). Thus, mucosal secretions accumulate leading to a greater risk of bacterial superinfection [6]. Since the normal turnover time for hair cells is 3 weeks, recurrence of the inflammation does not permit for normalization of the cell ratio within the nasal mucosa thus creating a self-maintaining vicious circle [9].

6.3

I mmunologic Aspects of the Nasal and Paranasal Sinus Mucosa

The respiratory epithelium, previously regarded as a physical barrier, is greatly engaged in the nasal-associated lymphoid tissue (NALT); actually, the epithelial cells express major histocompatibility complex class II antigens, and Langerhans-type dendritic cells in the submucosal layer can present antigens to and trigger T-lymphocytes by interleukin 1 (IL-1) [10]. In normal mucosa, both T-suppressor and T-helper cells can be found, yet these are functionally inactive, which can be shown by the absence of the IL-2 receptor [11]. B-lymphocytes primarily generate IgA, develop in the Waldeyer ring, and after that they move to the NALT tissue, settle down in the lamina propria [12]. Dimerized sIgA through the secretory fragment are released from the mucosal film, in which they inhibit the absorption of inspired microorganisms [13]. IgG is produced in NALT and via plasmatic filtration, gets to the

subepithelial layer similar in concentration to IgA, but rises if there is inflammation. IgG can work with complement thereby increasing phagocytosis and antibody-mediated cytotoxicity [14]. Cells providing IgD and IgM are also found, while plasma cells providing IgE are not normally present in the mucosa, but may be produced when there is allergy [15]. The various pathogenic elements of allergic inflammation, like the hyperproduction of IgE, the increased discharge of mediators, and the specific tissue hyperreactivity, are now universally accepted [16]. Actually, allergic symptoms are just the last stage of an immunological process creating a state of atopy, resulting in a clinical sensitization which ultimately turns into a disorder. The transition from one state to the other is essential although duration varies in each individual. Atopy is genetically carried by means of a complicated pattern with variable penetrance [17]. Sensitization begins once T-helper type 2 (Th2) cells are activated to release cytokines (IL-4, IL-5, IL-12, IL-13, etc.), which stimulate the transformation of B-cells into plasma cells and the release of IgE and IL-5. IL-5 results in differentiation and maturation of eosinophils which have a significant role in the allergic inflammation. Th2 also releases IL-9 which will enhance the IgE response and the allergic inflammation within the airway [18]. An allergic condition is defined by an IgE-mediated immunologic response (type I) which occurs when the Fc portion of IgE, bound to high-affinity receptors on the mast cell surface, are crosslinked by multivalent antigen, triggering degranulation. Within minutes, both preformed mediators, such as histamine and tryptase, cause the immediate or early phase response, whereas production of other newly synthesized mediators, such as leukotrienes (LTC4, LTD4, etc.), prostaglandins (PGD2, PGE2, and PGF2), eosinophil chemotactic factor, and platelet-activating factor, result in the late response after 6–12 h [18]. The late phase response involves the recruitment of inflammatory cells (basophils, eosinophils, T-lymphocytes) and group 2 innate lymphoid cells (ILC2s), as a result of the hyperexpression of adhesion molecules (intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule (VCAM-1), and E-Selectin) which retains all these cells in situ [3, 19], and the presence of various chemokines and cytokines [19, 20]. These mediators result in vasodilatation in the end organ, enhance vascular permeability, the release of muciparous secretions, and stimulate nerve endings which cause nasal symptoms (nasal blockage, runny nose, itchiness, and sneezing) [21]. The clinicopathologic details demonstrate the allergenic character; allergic rhinitis (AR) due to pollens is mostly seasonal, whereas AR caused by animal epithelium or house dust mite is generally perennial [22].

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6  Physiology of the Nose and Paranasal Sinuses

6.4

Nasal Cycle

The nasal cycle is the alternation of resistance between the two sides of the nose upon what additional changes are superimposed. In exercise and hyperpnoea, the resistance of the nasal airflow is diminished, most probably due to vascular decongestion. Present research of the crutch reflex (the ipsilateral nasal congestion resulting from stimulation of the axilla) demonstrate that several reflex inputs which go to the nose may be unilateral [23]. The volume of the two nasal cavities alternates on a 50-min to 4-h cycle in no less than 80% of people [24]. The cross-section and resistance of the nasal air passage in total are retained when one nostril dilates and the other constricts [25]. This endogenous circadian rhythm is not fully understood; it is probably under autonomic control, thus may be changed with medications, and its influences tend to be amplified by allergic, infectious, and non-allergic circumstances which result in the enhanced thickness of the lamina propria and mucous secretions. Nasal congestion and decongestion switch from one to the other cavity as a natural cycle, even though unilateral resistances may change among significant blockage to ideal patency [26, 27]. The amplitude and rate of the ongoing cycle are not regular, yet the rate is usually assessed in hours [28]. Slight fluctuations of shorter periods are superimposed on the advancement of the cycle; however, the reciprocality among sides is pretty constant, and the mixed resistance stays pretty constant [5]. The nasal cycle occurs in around 80% of the adults, and it can temporarily be absent. This cycle has also been identified in children and infants, but the frequency and reciprocation among sides are more irregular compared to adults. An identical ongoing cycle has been shown in cats, dogs, pigs, rabbits, and rats, that, similar to humans, show erectile nasal tissue [28].

6.5

Mucociliary Clearance

Mucociliary clearance is an important natural defence mechanism towards inhaled microbes and irritants [29]. During respiration inhaled particles, like dust and bacteria, ultimately get to the respiratory tract. In response to the continuous risk of inflammation and infection, the airway tract has developed various innate defence mechanisms [30]. In people, cilia are located along the respiratory pathway, such as the middle ear and the sinuses [31]. Each cilium is around 6  μm long and possesses a diameter of 250  nm. The amount of cilia within the air passages reaches the degree of 109cilia/cm2 generally, lengthening and getting more densely lined within the proximal respiratory tract compared to the bronchioles

[32]. The purpose of the cilia in the respiratory system is to beat in a synchronized way, thus pushing mucous and particles which are caught inside the mucous to the pharynx, and get swallowed [30]. The mucous is removed off the cilia via the periciliary fluid coating, which contains two principal purposes. Due to its low viscosity, it enables the cilia to beat quickly, and it inhibits the glycoproteins of the mucous layer from sticking on the glycocalyx of the epithelial apical membrane [33]. In normal people, mucous within the air passages consists of 97% water and just 3% solids, of which mucins form roughly around 30% (while the remaining is non-mucin proteins, lipids, salts, and cellular debris). In such a composition, the mucous is going to gain a consistency similar to an egg white that could simply be removed away from the air passages by the beating of the cilia. Nevertheless, the equilibrium of liquids may be disturbed either by mucin hypersecretion or dysregulation of the amount of surface fluid, providing a denser and stretchier mucous, that is harder to remove from the air passages [34].

6.6

Functions of the Nose

The functions of the nose can be classified as follows: [1] airway [35], [2] filtration of the airway [36], [3] air conditioning, [4] olfaction, [5] effects on speech, [6] reflex functions, and [7] common factors that impact the nasal circulation of blood [35].

6.6.1 Nasal Airway The nasal area is among the most crucial factors for the resistance of air passage; it has been shown to produce 30–50% of the overall resistance to the inspired air [35]. The air first moves upwards into the nares, due to its location and the anterior nasal valve. Then, the airflow curves backwards about 90°, and afterwards passes to the nasopharynx. From here it travels downwards 90° through the pharynx and larynx, eventually passing through the trachea to reach the lungs. The anterior nasal valve is placed 1.5–2 cm posterior to the anterior nares and is the narrowest part of the upper respiratory tract. This narrow part of the upper respiratory tract enables a greater exposure of air to the mucosal surfaces [1].

6.6.2 Filtration of the Airway While we take the air in, the nasal area is regularly subjected to particles and microorganisms inspired such as viruses, bacteria, and fungus. The respiratory system has

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designed a number of defence mechanisms to overcome this constant attack. Bigger debris is caught by means of the nasal vibrissae (hairs in the entry of the nose). Smallersized debris tends to be caught in the mucous, which is regarded as one of the first defences of the respiratory tract. Mucous is designed to capture inhaled contaminants which include microorganisms that are eventually cleaned from the nasal passage. Nasal secretions consist of enzymes, anti-microbial mediators, and immune cells that eliminate undesired viruses and bacteria as well. Most mucous is pushed towards the throat to be swallowed and eliminated by the products within the stomach. Mucous that contains pathogenic agents and debris may sometimes be coughed up or sneezed out [36].

6.6.3 Conditioning of Breathed Air Air within the nasopharynx is almost 100% humid. Breathing out is, in effect, the reverse of breathing in, with a low volume of air that has been conditioned already during inspiration passing from out of the anatomical dead space represented by the trachea and bronchus and over the mucosa of the throat and nose. These mucosae had already been cooled by air during inspiration, but now as the air returns, its heat and moisture is given back to the mucosa [34]. Moisture evaporates from the surface of the mucosa, causing water to be absorbed into the air up to 75–80% saturation. Inhaled air is heated to 36 °C through heat exchange from blood vessels forming the abundant circulation of the nose, most markedly in the region of the lower conchae [1]. In this way, a typical adult human uses 680 mL water (representing around 20% of dietary input) to humidify the 14,000 litres of air (at least) breathed daily [37]. Sniffing plays a vital function by redirecting air towards the top of the nasal cavity, thereby bringing it into further contact with the olfactory mucosa [1].

M. E. Dinç et al.

6.6.4.1 Olfactory Epithelium Three distinct cell populations comprise the olfactory epithelium: basal, support, and olfactory receptor cells. Basal cells are those stem cells with the potential to differentiate into olfactory receptor cells (Fig. 6.2) [40]. In respect of possessing the ability to turn over and produce fresh neurones from less committed precursor cells, the olfactory system is unique, since the rest of the nervous system in adulthood lacks this capability. Dotted between receptor cells are the support cells, bearing multiple microvilli and granules for secretion on their mucosal surface [40]. The olfactory epithelial cells have downward-pointing cilia which are swathed in a coat of mucus of 60 μm thickness [41]. The mucus itself is produced by Bowman’s glands located intraepithelially and contains many lipids. It functions to ensure the cleanliness of the receptor portions facing outwards into the lumen. Given that only odorous compounds which enter the mucus from the surrounding air are able to stimulate the olfactory receptors to produce signals the brain interprets as smells, the lipids are vital to ensure such a process can occur. An olfactory receptor neurone sports on average 8–20 cilia, 30–200 μm long thin flagella form processes about 30–200  μm in length. Smell-bearing molecules bind to receptors on the cilia as the first stage in signal transduction [39]. Basal cells are located at the lowest level of the epithelium and multiply by mitotic divisions prior to eventual differentiation into olfactory receptor neurones, which have a lifespan of approximately 40 days. There are also a number of cells possessing a pale yellow pigmentation. In canine species, they are darker hued, ranging from dark yellow to brown. It is thought that the darker the colour, the more sensitive they are to smell [39]. Receptor cells have a bipolar morphology, possessing a slender dendritic extension with ending bearing cilia that emerge from the olfactory vesicle, while the axonic portion terminates as the first Cranial Nerve.

6.6.4 Olfaction The turbinates act to drive inhaled air upwards and backwards towards the olfactory membrane. Within an area a mere 2 cm wide, considerably in excess of 100 million olfactory receptor-bearing cells are found. Olfactory vesicles, which consist of kinocilia, are produced here and they transduce the olfactory stimulus into a neuronal impulse. The sense of smell is more highly developed in other mammals, e.g. rodents [38]. The human olfactory membranes are bilateral and each occupies a region approximately 2.5 cm2 in extent, bearing approximately 50 million primary sensory receptor cells in total [39].

Fig. 6.2  Olfactory receptors

6  Physiology of the Nose and Paranasal Sinuses

The cilia are the sites of origin for signal transmission to the olfactory system [38]. The vomeronasal organ, located bilaterally at the lower extremity of the front portion of the nasal septum, where cartilage and bony portions abut each other, is a structure consisting of membranes. It is believed to respond to inter-animal signalling molecules referred to as pheromones, which, although not consciously perceived by humans through the usual olfactory system, nonetheless can produce alterations in the autonomic nervous and hormonal systems, as well as psychological alterations. Trigeminal projections passing to the back of the nose interior are sensitive to noxious substances [38]. Olfactory neurones terminate outside the body, interacting with smell-bearing molecules at the epithelial surface. At the deep epithelial surface, the axonic projections are bundled, 10–100 together, prior to piercing the ethmoidal cribriform plate and finally synapsing in the olfactory bulb of the central nervous system. These synapses are termed glomeruli. Glomeruli form clusters which in turn are connected to specific mitral cells. Taking rabbits as a model organism, 26,000 of their receptor cells synapse in 200 glomeruli. Then, 25 glomeruli feed into a single mitral cell. Thus, approximately 1000 receptor cells contribute their input to a single mitral cell [39]. Viewed in physiological terms, this adaptation allows for a heightened olfactory response by the brain. The summated signal is then conveyed upwards in the central nervous system, e.g. to the cortico-medial amygdala via the olfactory tract, where decoding leads to the stimulus being understood in olfactory terms and responses being initiated [39].

6.6.5 Speech The nasal area produces resonance of the voice. The nasal consonants M, N, and NC are created by the airflow coming from the larynx vibrating inside the nose [35]. Hypernasal speech, hyperrhinolalia, or rhinolalia aperta is improper excessive air flowing through the nose during speech, especially with syllables which begin with plosive and fricative consonants. Types of hypernasal speech include those arising from a cleft palate and velopharyngeal insufficiency. Hyponasal speech, denasalization, or rhinolalia clausa is an insufficient appropriate air flow through the nose in the course of speech. Some examples of the conditions that cause hyponasal speech are adenoidal hypertrophy, allergic rhinitis, septal deviation, rhinosinusitis, and turbinate hypertrophy [42].

6.6.6 Nasal Reflex Functions Nasal reflexes offer an opportunity to delineate the distinct subjective and objective factors that contribute to patient

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symptoms and local mucosal, systemic, and central nervous system afferent and efferent mechanisms. However, a major issue continues to be the surprising lack of consensus on the definition of specific non-allergic syndromes and nasal symptoms [43, 44]. The activation of trigeminal chemosensory neurons has been difficult to understand without information about the subpopulations of nociceptive nerves and activating ion channels (e.g. TRP). Challenge studies with multiple chemicals using cross-desensitization paradigms in anosmic subjects have proposed that there may be 6, 12, or more distinct chemosensory trigeminal neuron subtypes [45].

6.6.6.1 Trigemino-Cardiac Reflex The trigemino-cardiac reflex (TCR) presents as a rapid onset bradycardic episode or other abnormal cardiac rhythm mediated parasympathetically, hypotensive arterial tone mediated sympathetically, apnoea, and excessive motility within the stomach. It occurs when the trigeminal sensory division is stimulated [23]. It forms a component of the diving reflex [46]. It is frequently noted during ophthalmological or periocular surgical procedures, but can also result from inadvertently stimulating the central section of Cranial Nerve V (CNV) when operating near to the cerebello-pontine angle. A naso-cardiac reflex is a variety of TCR resulting from nervous excitation in the nasal or sinusal regions. A study involving 80 healthy volunteers, whose mucosae overlying the middle turbinate were irritated with 25% ammonia, found that virtually all of the volunteers exhibited a naso-­ cardiac reflexive response [47]. It is hypothesized that TCR occurs due to a reflex arc that consists of Cranial Nerve V on the afferent side of sensory fibres which go through the trigeminal ganglion before synapsing in the sensory nucleus of CNV [48, 49]. 6.6.6.2 Nasobronchial Reflexes Just as the TCR is part of the diving reflex, so is the nasobronchial reflex. If the head is placed under cold water, apnoea (halting of breathing), laryngospasm, and bronchoconstriction occur instantaneously. The nasocardiac component of the reflex consists of heart slowing, lower cardiac output, and constriction of the vascular beds of the skin, musculature, gut, and kidney [50–52]. A study of patients who had undergone one-sided transection of CNV in an attempt to control pain in trigeminal neuralgia gave the clue necessary for mapping out the afferent arc of the nasocardiac reflex [53]. Sand dust in the nostrils of the unaffected side gave a burning sensation in the nose lining and provoked a nasolacrimal response, accompanied by marked pulmonary airway constriction, while applying the same stimulus on the operated side produced no reaction either within the nose or in the airway. Further studies localized the afferent pathway to the maxillary division of the trigeminal nerve, since neither the

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ethmoid nor olfactory nerves produced such results [54]. Linkages between nasal and pulmonary physiology, as exemplified by neurogenic and neurobronchial reflexes, have been the subject of research in asthmology as well as in research into rhinitis, both allergy and non-allergy related [55, 56].

6.6.6.3 Nasogastric Reflex It is possible the afferent and efferent arms of the nasogastric reflex may be CNV and CNX (vagus) [57], and they may be connected at the pontomedullary level within the CNS. Sensory input originating in the nose enters the general somatic afferent region of the lower brain via the pontomedullary trigeminal nuclei, influencing perhaps the closely situated nucleus solitarius. These pathways are thought to utilize glutamine and transmitters other than NMDA (N-methyl-D-­aspartate) for signalling. A second arm reaches the vagal dorsal motor nucleus and accounts for the symptoms caused by vagal motor outflow, such as retching, gastric dilatation, and increased acidity and loss of appetite, alongside the dilatation of the physiological sphincter at the gastric entrance [58].

6.6.7 Factors That Affect Nasal Blood Flow Numerous distinct general and local variables may influence the nasal vasomotor response. Local causes involve alterations in the surrounding humidity and temperature, the topical usage of vasoactive drugs, compression of large neck veins externally, inflammation, and trauma. Normally, nasal mucosa aims to restore the homeostatic process in the nasopharynx and tracheobronchial airway. Medications having sympathomimetic actions have been long used topically on the nasal mucosa to cause shrinkage with blanching. Parasympathomimetic medications result in congestion in the nasal mucosa and reduce nasal airflow while increasing the amount of nasal secretions [35].

References 1. Archer SM.  Nasal Physiology. In: Meyers AD (Ed.). Medscape. http://emedicine.medscape.com/article/874771-overview#showall. Accessed 6 July 2015. 2. Gelardi M, Cassano P, Cassano M, Fiorella ML.  Nasal cytology: description of hyperchromatic supranuclear stria as a possible marker for the anatomical and functional integrity of the ciliated cell. Am J Rhinol. 2003;17(5):263–8. 3. Rosenwasser LJ. Current understanding of the pathophysiology of allergic rhinitis. Immunol Allergy Clin N Am. 2011;31:433–9. 4. Barata LT, Ying S, Meng Q, et  al. IL-4-and IL-5-positive T lymphocytes, eosinophils, and mast cells in allergen-induced late-phase cutaneous reactions in atopic subjects. J Allergy Clin Immunol. 1998;101:222–30.

M. E. Dinç et al. 5. Cole P.  Physiology of the nose and paranasal sinuses. Clin Rev Allergy Immunol. 1998. Spring-Summer;16(1–2):25–54. 6. Pelikan Z, Pelikan-Filipek M.  Cytologic changes in the nasal secretions during the late nasal response. J Allergy Clin Immunol. 1989;83:1068–79. 7. Jorissen M, Cassiman J-J.  Relevance of the ciliary ultrastructure in primary and secondary dyskinesia: a review. Am J Rhinol. 1991;5(3):91–101. 8. Gelardi M, Fiorella ML, Leo G, Incorvaia C. Cytology in the diagnosis of rhinosinusitis. Pediatr Allergy Immunol. 2007;18:50–2. 9. Canonica GW, Compalati E.  Minimal persistent inflammation in allergic rhinitis: implications for current treatment strategies. Clin Exp Immunol. 2009;158:260–71. 10. Hellquist HB, Olsen KE, Irander K, Karlsson E, Odkvist LM.  Langerhans cells and subsets of lymphocytes in the nasal mucosa. APMIS. 1991;99:449–54. 11. Igarashi Y, Kaliner MA, Hausfeld JN, Irani AA, Schwartz LB, White MV.  Quantification of resident inflammatory cells in the human nasal mucosa. J Allergy Clin Immunol. 1993;91:1082–93. 12. Pawankar R, Okuda MA. Comparative study of the characteristics of intraepithelial and lamina propria lymphocytes of the human nasal mucosa. Allergy. 1993;48:99–105. 13. Kurono Y, Shimamura K, Shigemi H, Mogi G. Inhibition of bacterial adherence by nasopharyngeal secretions. Ann Otol Rhinol Laryngol. 1991;100:455–8. 14. Ivarsson M, Lundberg C. Phagocytosis in the nasopharyngeal secretion by cells from the adenoid. Acta Otolaryngol. 2001;121:517–22. 15. Gelardi M, Incorvaia C, Passalacqua G, Quaranta N, Frati F. The classification of allergic rhinitis and its cytological correlate. Allergy. 2011;66:1624–5. 16. Pawankar R.  Inflammatory mechanisms in allergic rhinitis. Curr Opin Allergy Clin Immunol. 2007;7:1–4. 17. Bernstein JA. Allergic and mixed rhintis: epidemiology and natural history. Allergy Asthma Proc. 2010;31:365–9. 18. Hauber HP, Bergeron C, Hamid Q. IL-9 in allergic inflammation. Int Arch Allergy Immunol. 2004;134:79–87. 19. Passalacqua G, Ciprandi G, Canonica GW. United airways disease: therapeutic aspects. Thorax. 2000;55:26–7. 20. Eifan AO, Durham SR. Pathogenesis of rhinitis. Clin Exp Allergy. 2016;46(9):1139–51. 21. Brozek JL, Bousquet J, Baena-Cagnani CE, et  al. Global allergy and asthma European network, grading of recommendations assessment, development and evaluation working group. Allergic rhinitis and its impact on asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126:466–76. 22. Gelardi M, Marchisio P, Caimmi D, Incorvaia C, Albertario G, Bianchini S, et  al. Pathophysiology, favoring factors, and associated disorders in otorhinosinusology. Pediatr Allergy Immunol. 2012;23:5–16. https://doi.org/10.1111/j.1399-3038.2012.01323.x. 23. Widdicombe JG.  The physiology of the nose. Clin Chest Med. 1986;7(2):159–70. 24. Hasegawa M, Kern EB. The human nasal cycle. Mayo Clin Proc. 1977;52(1):28–34. 25. Kennedy DW, Zinreich SJ, Kumar AJ, et al. Physiologic mucosal changes within the nose and the ethmoid sinus: imaging of the nasal cycle by MRI. Laryngoscope. 1988;98(9):928–33. 26. Cole P, Haight JSJ. Posture and the nasal cycle. Ann Otol Rhinol Laryngol. 1986;95:233. 27. Stocksted P.  Rhinometric measurements for determination of the nasal cycle. Acta Otolaryngol (Stockh). 1953.;(Suppl 109;43:159–75. 28. Cole P. The respiratory role of the upper airways. St. Louis, MO: Mosby; 1993. p. 1–59. 29. Munkholm M, Mortensen J.  Mucociliary clearance: pathophysiologicalaspects. Clin Physiol Funct Imaging. 2014;34(3):171–7.

6  Physiology of the Nose and Paranasal Sinuses 30. Wanner A, Salathe M, O’Riordan TG. Mucociliary clearance in the airways. Am J Respir Crit Care Med. 1996;154:1868–902. 31. Meeks M, Bush A.  Primary ciliary dyskinesia (PCD). Pediatr Pulmonol. 2000;29:307–16. 32. Livraghi A, Randell SH. Cystic fibrosis and other respiratory diseases of impaired mucus clearance. Toxicol Pathol. 2007;35:116–29. 33. Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest. 2002;109:571–7. 34. Fahy JV, Dickey BF.  Airway mucus function and dysfunction. N Engl J Med. 2010;363:2233–47. 35. Geurkink N.  Nasalanatomy, physiology, and function. J Allergy Clin Immunol. 1983;72(2):123–8. 36. Jeremiah A, Cohen N.  Nasal physiology. American Rhinologic Society. http://care.american-rhinologic.org/nasal_physiology. Accessed 6 July 2015. 37. Naclerio RM, Pinto J, Assanasen P, Baroody FM. Observations on the ability of the nose to warm and humidify inspired air. Rhinology. 2007;45(2):102–11. 38. Vokshoor A.  Olfactory System Anatomy. In: Meyers AD (Ed.). Medscape. http://emedicine.medscape.com/article/835585-overview. Accessed 6 July 2015. 39. Leffingwell JC, Olfaction. Leffingwell & Associates. http://www. leffingwell.com/olfaction.htm. Accessed 6 July 2015. 40. Morrison EE, Costanzo RM. Morphology of the human olfactory epithelium. J Comp Neurol. 1990;297(1):1–13. 41. Ohloff G. Scent and fragrances. Berlin: Springer; 1994. 42. Nasal voice. Wikipedia. https://en.wikipedia.org/wiki/Nasal_voice. Accessed 6 July 2015. 43. Raphael GD, Meredith SD, Baraniuk JN, Kaliner M. Nasal reflexes. Am J Rhinol. 1988;2:8–12. 44. Eccles R.  Pathophysiology of nasal symptoms. Am J Rhinol. 2000;14:335–8. 45. Green BG, Mason JR, Kare MR (editors). Chemical senses, Vol. 2, irritation. Marcel Dekker. New York; 1990, pp 141–170.

63 46. Kratschmer F.  On reflexes from the nasal mucous membrane on respiration and circulation. Respir Physiol. 2001;127:93–104. 47. Betlejewski S, Betlejewski A, Burduk D, Owczarek A.  Nasal-­ cardiac reflex. Otolaryngol Pol. 2003;57:613–8. 48. Schaller B, Probst R, Strebel S, Gratzl O.  Trigeminocardiac reflex during surgery in the cerebellopontine angle. J Neurosurg. 1999;90:215–20. 49. Schaller B.  Trigeminocardiac reflex: a clinical phenomenon or a new physiological entity? J Neurol. 2004;251:658–65. 50. Patow CA, Kaliner M.  Nasal and cardiopulmonary reflexes. Eur Nose Throat J. 1984;63:78. 51. Widdicombe JG.  Reflexes from the upper respiratory tract. In: Fishman AP, Cherniak NS, Widdicombe JG, Geiger SR (eds). Handbook of physiology. Section 3. The respiratory system. Volume II, control of breathing, part 1. American Physiological Society. Washington, DC. 1986, pp. 363–394. 52. Mygind N.  Non-immunological factors. In: Mygind N. (edi tor) Nasal allergy. Oxford. Blackwell Scientific. Oxford. 1978, pp. 140–154. 53. Kaufman J, Chen JC, Wright GW. The effect of trigeminal resection on reflex bronchoconstriction after nasal and nasopharyngeal irritation in man. Am Rev Respir Dis. 1970;101:768–9. 54. Allen WF. Effect of various inhaled vapors on respiration and blood pressure in anesthetized, unanesthetized, sleeping, and anosmic subjects. Am J Phys. 1929;88:620–32. 55. Togias A.  Mechanisms of nose-lung interaction. Allergy. 1999;54(Suppl 57):94–105. 56. Undem BJ, McAlexander M, Hunter DD.  Neurobiology of the upper and lower airways. Allergy. 1999;54(Suppl 57):81–93. 57. Shoja MM, Tubbs RS, Ansarin K, Farahani RM.  Proposal for the existence of a nasogastric reflex in humans, as a potential cause of upper gastrointestinal symptoms. Med Hypotheses. 2007;69(2):346–8. Epub 2007 Feb 28. 58. Schaller B. Trigemino-cardiac reflex during transsphenoidal surgery for pituitary adenomas. Clin Neurol Neurosurg. 2005;107:468–74.

7

Mucociliary Clearance and Its Importance Deniz Tuna Edizer, Ozgur Yigit, and Michael Rudenko

7.1

Introduction

Nasal airway, which is exposed to a variety of noxious agents, transports tremendous amount of air into the lungs during normal respiration. Nasal cavity is lined mostly with the ciliated pseudostratified columnar epithelium, whereas the paranasal sinuses are lined with the ciliated simple columnar epithelium [1]. Goblet cells and ciliated cells predominate in the epithelial layer [2]. Submucosal layer contains seromucous glands which also participate in production of the secretory blanket together with the goblet cells [3]. Nasal mucosa is considered as the first-line defence against airborne particles through its mucosal surface which maintains intimate contact with the environment [4, 5]. There are many mechanisms that are acting together to protect the host: mucosal barrier function, mucociliary clearance (MCC), inherent phagocytes, and secretion of a variety of proteins. Airway surface is covered with a twolayered coating composed of periciliary layer (periciliary fluid) and mucus layer [6]. Cilia of the epithelial cells move in a coordinated fashion in order to propel the pathogens and particles. These cilia beat frequently in the periciliary layer of low-viscosity fluid [4]. On top of the cilia is the mucus layer composed of water, carbohydrates, proteins, and lipids [6]. This content is fundamental to its protective function [7]. Mucus layer, which is produced by the goblet cells of the respiratory epithelium and propelled by the ciliary action, has the ability to trap the inhaled particles and infectious debris [2, 4] and has a viscous consistency [2, 8].

D. T. Edizer (*) · O. Yigit Department of Otorhinolaryngology, University of Health Sciences, Istanbul Training and Research Hospital, Istanbul, Turkey e-mail: [email protected] M. Rudenko The London Allergy and Immunology Centre, London, UK

MCC mechanism transports this mucus from the nasal cavity to the pharynxandhas, a well-established defence function [7, 9] which is considered as a part of the innate immunity [10, 11]. MCC is driven by the coordinated action of the cilia. The coating of the airway surface is also called airway surface fluid (ASL) [9] and airway epithelia are known to have a role in regulation of the volume and/or composition of the ASL [12, 13]. Paranasal sinuses depend solely on MCC mechanism to clear mucus, whereas nasal cavity takes the advantages of sneeze and cough reflexes in addition to MCC [2]. Cough and sneezing may become even more prominent in mucus transport in the presence of pathologic conditions [14]. Coordinated ciliary activity of the epithelium along with intact mucus and periciliary layer production is needed for an effective MCC [2]. Failure of the ciliary activity and/or the production of the mucus-periciliary layer lead to serious disorders [10, 15]. Sears et al. reported that an efficient MCC requires proper interaction of salt and water transport, mucin synthesis, and ciliary beat function [10]. The control of mucociliary clearance is intimately related to autonomic activity [7]. Parasympathetic stimulation causes nasal vasodilation and increases nasal secretions whereas sympathetic stimulation attenuates this effect [16]. MCC is especially important in the first-line defence against invading antigens [17]. In patients with abnormal MCC such as cystic fibrosis (CF) or primary ciliary dyskinesia (PCD), recurrent airway infections dominate the clinical picture.

7.2

The Cilia

Each respiratory epithelial cell contains 50–200 cilia [1, 14]. The length of the cilia ranges between 5 and 7 μm, and the diameter is about 0.2–0.3 μm [15]. Cilia are located in the apical surface of the epithelial cells and are anchored to the basal bodies at the base immediately beneath the cell membrane. The cilium has a highly organised microtubule structure. The inner cytoskeletal part of the cilia is called axoneme

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and this core consists of 9 + 2 pattern of microtubules. This pattern of nine peripheral doublet microtubules and two central singlet microtubules is unique [14]. The microtubules are made of protofilaments which consist of α and β tubulin dimers [1]. In peripheral microtubules, α tubulin consists of a complete circle of 13 protofilaments, whereas β tubulin has an incomplete circle of 10 protofilaments, hence the term doublet microtubule. Peripheral pairs share a common wall, and the central pair is separated from each other [1, 15, 18]. The peripheral microtubule pairs are linked to each other via nexin bridges and to the central pair via radial spokes. Two dynein arms project from the α tubulin: outer and inner dynein arms. Dynein arms are the extensions from the surface of the peripheral pairs and known to have ATPase activity. These two dynein arms along with the nexin bridge provide interaction of the adjacent peripheral microtubules which in turn results in bending of the cilia [19, 20]. In the nasal cavity, as well as in the lower respiratory tract, the cilia have a whip-like motion which causes the mucus layer to move at a rate of 3–25  mm/min [3]. This motion clears the respiratory tract from the invading particles. The cilium moves forward with a sudden effective stroke, with a rate of 10–20 times per second (Hz), followed by a slower backward movement (recovery stroke) [3, 20, 21]. The cilia are almost fully extended during the forward stroke so that the distal tip gets contact with the mucus (gel) layer. This orientation transmits the directional force to the mucus layer. During the recovery, backward stroke, the cilia bend 90° to the starting point within the periciliary fluid [22]. Switching from the forward stroke to the backward stroke was suggested to occur at constant angles or particular positions of the cilia [23, 24]. The axoneme can be thought to be divided into halves by the central microtubule doublets. The dynein arms of one side are generally more active during the effective stroke and those of the other side are more active during the recovery stroke [2, 25]. The stroke orientation is controlled by the basal body. Basal body of the cilium is involved in ciliogenesis and in regulating cilia polarity [26]. The forward movement propels the mucus layer in the direction of the ciliary movement. Since each ciliated epithelial cell has as many as 200 cilia oriented in the same direction, the result is an effective mucociliary movement in a particular direction [4]. The slower backward ciliary movement, on the other hand, has almost no effect on the mucus layer. The beating movement of the cilia is metachronous rather than synchronous so that it carries the overlying mucus (gel) layer to the distal part of the airway [14, 22]. Metachronous coordination, which is extremely important in mucus transport, results in a continuous movement of mucus [21]. It was demonstrated long before that the clearance pathways of the paranasal sinuses were predetermined toward the ostia [27]. The ostia are not gravity dependent and even in the presence of surgical interventions (antrostomy), drainage patterns fol-

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low the natural ostia [22]. Dynein mediated sliding of the peripheral microtubule doublets is the widely accepted model of cilia movement. This model proposes that the dynein arms attached to one microtubule doublet contact to the more basal part of the adjacent doublet and this leads to bending of the cilium [15]. Dynein arms convert the chemical energy into mechanical energy for sliding of the microtubule doublets [15]. Release of energy from the dynein arms leads to interaction of the nearby doublets [19, 20]. It was proposed that the phosphorylation of the outer dynein arms regulates the frequency, whereas phosphorylation of the inner dynein arms regulates the waveform pattern of ciliary beating [27, 28]. The exact function of the radial spokes connecting the outer doubets to the central pair has not been discovered, but they are thought to be involved in regionally limiting the sliding movement and thus converting the sliding motion into a bending motion [29]. Ciliary interaction is thought to be driven by gap junction connections between the epithelial cells [30] or a hydrodynamic wave that results in a timed coordination of nearby cilia [31]. Functional gap junctions of connexin 43 are present in nasal mucosa and were proposed to be involved in ciliary beating [30]. Hydrodynamic wave theory, on the other hand, assumes that the cilia are coupled to one another through the medium between them without direct contact [31]. Hydrodynamic coupling provides a coordination movement given that the gap between the cilia is less than 10 μm. Once the normal MCC mechanisms are disrupted, mucus accumulation and stasis follow, and this leads to secondary bacterial infections. Movement of the mucus layer by the beating action of cilia is responsible for the hygiene of the airway [3]. The paranasal sinuses are usually sterile due to rapid removal of bacteria by the action of cilia and the effects of immune system [3]. Abnormal ciliary motion results in persistent exposure of the airway to the antigens, and the ongoing inflammatory state manifests as sinusitis and/or bronchiectasia. Mucociliary clearance is most frequently disrupted in upper airway infections and inflammations. Inherited disorders of the mucociliary system are generally due to either ciliary dysfunction, as seen in primary ciliary dyskinesia, or to increased viscosity of the mucus secretion, as seen in cystic fibrosis. Ciliary beat frequency (CBF) can be affected by a variety of environmental and host factors. An increase in intracellular acidity decreases CBF, while a decrease in acidity increases CBF [32]. Temperature changes also affect the CBF. Green et al. reported that CBF had increased linearly between 19 and 32 °C, had reached a plateau between 32 and 40 °C, and had begun to decline above 40 °C [33]. Beta-2 adrenergic and muscarinic cholinergic agonists have been demonstrated to increase CBF [34]. Sanderson et al. reported that mechanical stimulation of the cultured ciliated cells resulted in a transitory increase of 20% or more in CBF [35].

7  Mucociliary Clearance and Its Importance

7.3

Mucus Layer

Respiratory blanket is composed of two layers: the mucus layer (gel) and the periciliary fluid (sol). The former is more viscous compared to the periciliary fluid. In some papers, these two layers are collectively termed as the respiratory mucus. Mucus layer is produced by goblet cells and submucosal glands. Water (95–97%), mucin (glycoprotein), immunoglobulins, albumin, lysozyme, and lactoferrin are the main components of the mucus layer. Periciliary layer is produced by the nonciliated epithelial cells, and it contains minimal glycoproteins and proteins along with water. As stated earlier, the vast majority of the ciliary movement occurs in the periciliary fluid [36]. The composition and the thickness of the periciliary fluid are critical factors for proper mucociliary transport (MCT) function. If the PCF is critically thin, the cilia may get contact with mucus layer which may lead to impairment of mucus clearance [37]. Mucus glycoprotein, which has a molecular weight of 0.5–20 MDa, insulates the underlying mucosa, acts as a reservoir for humidification of the air, provides lubrication for passage of objects, and maintains hydration [38]. Plasma cells located in the mucosa produce both immunoglobulin G (IgG) and IgA. IgG performs its action in the mucosa itself, whereas IgA functions in the secretions, hence the name secretory IgA. Lysozyme and lactoferrin, produced by the serous cells of the submucosa, attack microorganisms and help to prevent mucosal infection. The viscosity of the mucus is influenced mostly by the active ion and water transport mechanisms of the epithelial layer and by the activity of the glands and goblet cells. Mucus production and structure are closely linked to cilia function. The content of the mucus is fundamental to its protective function [7]. Mucus must have a viscoelastic nature. The balance between viscosity and elasticity is necessary for optimal mucociliary clearance. Viscosity is described as resistance to flow, and elasticity can be defined as transmission of energy back to the object. The viscoelasticity of the mucus is influenced by many factors including the type of the glycoproteins, hydration and pH of the secretions, and ionic composition [39].

7.4

Impairment of Mucociliary Clearance

Cilia function and the characteristics of the mucus blanket directly influence the MCC. Abnormal cilia function impairs MCC and vice versa [1]. Primary ciliary dyskinesia is an inherited disease that results in abnormal ciliary structure and function [40]. Although PCD has genetic heterogeneity, the most common axonemal defect is related to outer dynein arms [41]. The influence of the composition and integrity of the ASF is best understood in cystic fibrosis. CF leads to a

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dehydrated and acidic mucus layer [42]. Antimicrobial function and MCC are impaired in CF. MCC may be impaired by both anatomic factors, including nasal septal deviations [43, 44] and physiological changes including nasal cycle [45]. Diurnal variations were also reported [46]. Multiple investigations demonstrated a marked decrease in sinonasal mucociliary clearance in patients with rhinosinusitis and allergic rhinitis [47–51]. Impaired mucociliary clearance has also been reported in patients with adenotonsillar hypertrophy [31, 52].

7.5

Measurement of Mucociliary Transport

Effective mucociliary clearance depends on both appropriate mucus/periciliary fluid production, and composition and coordinated ciliary activity [2, 43, 53]. Mucociliary transport can be measured by in vivo or in vitro methods (Table 7.1).

7.5.1 I n Vivo Measurement of Mucociliary Transport In vivo methods involve most frequently the saccharin transit time test and radioisotope investigations [6]. Saccharin test is a simple, inexpensive, and widely used method to evaluate the MCT [54]. It was originally developed by Andersen in [55]. Deitmer et  al. stated that water soluble nature of saccharin could influence the composition of the periciliary fluid and might lead to clearance changes [56]. Anionic resin was added to saccharin overcome this problem. 5 mg of particulate saccharin is placed on the inferior turbinate about 1.5  cm posterior to the nostril and the transit time from the placement of the particle until the subject reports the taste is measured. Transit time of 10–15 min is considered normal by many papers; however, time greater than 20 min is usually considered abnormal [2]. Cooperation of the subject is very important in this test since the individual reports the sweet taste of saccharin. Sneezing, sniffing, and nose blowing must be avoided during the test [6]. It is better not to perform the test in patients with severe rhinorrhoea [54]. To provide visual control, a colour (methylene or indigo blue) is frequently added to the saccharin. Table 7.1  Tests of mucociliary transport and ciliary activity Testing of mucociliary transport In vivo Saccharin test Scintigraphy Testing of ciliary activity In vivo Light scattering spectroscopy

In vitro Phase-contrast microscopy

In vitro Microscope photometry

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Identification of the dye in the oropharynx when the subject senses the taste provides a means of confirmation. If the subject does not report any taste sensation after 30 min, another saccharin should be placed on the tongue to unmask any abnormality in taste function [2]. The main disadvantage of the saccharin test is the reliance on the individual’s subjective sense of taste [57]. Technetium-99m (Tc-99m) radionuclide scanning is a more objective and precise method to evaluate MCT [57]. A suspension of Tc-99m labelled colloid (albumin) particles is placed on the inferior turbinate or on the nasal septum and radioactivity is recorded with a gamma camera. Images are captured every 30 s for a period of 10 min [2]. Sniffing and coughing do not influence this test, in contrast to saccharin test [58]. Many papers have reported an average velocity of 10.9 mm/min for normal population [43, 58, 59]. However, radioactivity disappears from the nasal cavity within 30 min [6]. Tc-99m scintigraphy was reported to have an excellent intratest and intraobserver reproducibility and a good interaobserver reliability [60]. Although Tc-99m radionuclide test is more objective than the saccharin test, it is more expensive and special equipment is needed [6]. An important disadvantage of radionuclide scanning is the potential for serious side effects. Although rhinoscintigraphy has the potential for radioactivity as a side effect, it is generally accepted as a safe, easy, and reliable method [42, 61].

7.5.2 Assessment of Ciliary Beat Frequency 7.5.2.1 Video-Endoscopy A group of ciliary epithelial cells (surgical specimen) are examined with a light microscope (100× magnification) connected to a video camera. A strobe light is emitted by the source and reflected by the epithelium. CBF is defined when the flashing sequence is identical to that of CBF [14]. It is a subjective ex vivo technique and has not gained popularity. 7.5.2.2 Video-Microscopy With high-speed video cameras, ex vivo CBF can be evaluated with light microscopy. It is possible to capture hundreds of frames per second [14]. Epithelium can be visualised from many directions, i.e. from above, laterally, and anteriorly [62]. It is a highly reliable method for evaluating CBF, since it has the ability to unmask inefficient beating pattern even in the presence of normal CBF [62]. Video-Coupled Photomultiplier and Photodiode Techniques These techniques detect changes in light intensity passing through the field of beating cilia. An indirect estimation of CBF is provided. 250–400 frames per second can be captured [21, 63]. Both systems convert the light fluctuations to

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voltage changes which are transferred to an oscilloscope and analysed by spectral analysis program [2, 63]. In the photomultiplier method, voltage signals, which are generated through interruption of the passage of the light by the moving cilia, were displayed on an oscilloscope. In the photodiode method, video images of the beating cilia are relayed to a high-resolution monitor. The photodiode sensor is held over the cilia displayed on the monitor. CBF is determined by the help of an oscilloscope and a spectrum analysis program [21]. Coordination of the ciliary beating and the rheologic properties of the mucus are not evaluated in measurements of CBF. These two factors have great contributions tomucociliar clearance along with ciliary beating [2, 64, 65]. Transmission electron microscopy can be used for determination of ciliary beat coordination [64, 66]. Cost and difficulty of obtaining the ideal section are the main drawbacks. Another method of evaluating the coordination of cilia beating was reported by Gamarra et al. [65]. The authors reported that, when cultured in their own mucus, nasal epithelial spheroids can rotate along their axis due to coordinated beating. Frog palate techniques provide a common approach for examining the rheology of the mucus [67–69]. Frog palate has a ciliated epithelium similar to mammals [14, 68]. Mucus is placed on the resected palate of the frog to determine the transport velocity [2]. Velocity of the mucus sample can then be compared to the mucus of the frog itself [14]. Simplicity and low cost of this method makes it a potential way to study the effects of experimental agents [69].

References 1. Gudis DA, Cohen NA. Cilia dysfunction. Otolaryngol Clin N Am. 2010;43:461–72. 2. Antunes MB, Cohen NA. Mucociliary clearance—a critical upper airway host defense mechanism and methods of assessment. Curr Opin Allergy Clin Immunol. 2007;7:5–10. 3. Physiology SPLE.  Mucociliary clearance and neural control. In: Kenneedy DW, Bolger WE, Zinreich SJ, editors. Diseases of the sinuses diagnosis and management. London: BC Decker; 2001. 4. Fokkens WJ, Scheeren RA.  Upper airway defence mechanisms. Paediatr Respir Rev. 2000;1:336–41. 5. Bartlett JA, Fischer AJ, PB MC Jr. Innate immune functions of the airway epithelium. Contrib Microbiol. 2008;15:147–63. 6. Pallanch J, Jorissen M. Objective assessment of nasal function. In: Flint PW, Haughey BH, Lund V, Niparko JK, Robbins KT, Thomas JR, Lesperance MM, editors. Cummings otolaryngology head and neck surgery. 6th ed. Philadelphia: Elsevier Saunders; 2015. 7. Lund VJ. Nasal physiology: neurochemical receptors, nasal cycle, and ciliary action. Allergy Asthma Proc. 1996;17:179–84. 8. Eccles R. The nose and control of nasal airflow. In: Adkinson NF, Bochner BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, O’Hehir RE, editors. Middleton’s allergy principles and practice. 8th ed. Philadelphia: Elsevier Saunders; 2014. 9. Matsui H, Randell SH, Peretti SW, Davis CW, Boucher RC. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J Clin Invest. 1998;102:1125–31.

7  Mucociliary Clearance and Its Importance 10. Sears PR, Yin WN, Ostrowski LE. Continuous mucociliary transport by primary human airway epithelial cells in vitro. Am J Physiol Lung Cell MolPhysiol. 2015;309:L99–108. 11. Hulse KE.  Immune mechanisms of chronic rhinosinusitis. Curr Allergy Asthma Rep. 2016;16(1):1. 12. Quinton PM.  Viscosity versus composition in airway pathology. Am J Respir Crit Care Med. 1994;149:6–7. 13. Kilburn KH. A hypothesis for pulmonary clearance and its implications. Am Rev Respir Dis. 1968;98:449–63. 14. Trindade SH, de Mello JF Jr, Mion Ode G, Lorenzi-Filho G, Macchione M, Guimarães ET, Saldiva PH.  Methods for studying mucociliary transport. Braz J Otorhinolaryngol. 2007;73:704–12. 15. Chen D, Ren J, Mei Y, Xu Y. The respiratory ciliary motion produced by dynein activity alone: a computational model of ciliary ultrastructure. Technol Health Care. 2015;23:S577–86. 16. Revington M, Lacroix JS, Potter EK.  Sympathetic and parasympathetic interaction in vascular and secretory control of the nasal mucosa in anaesthetized dogs. J Physiol. 1997;505:823–83. 17. Munkholm M, Mortensen J.  Mucociliary clearance: pathophysiological aspects. Clin Physiol Funct Imaging. 2014;34:171–7. 18. Shoemark A, Hogg C.  Electron tomography of respiratory cilia. Thorax. 2013;68:190–1. 19. Ueno H, Bui KH, Ishikawa T, Imai Y, Yamaguchi T, Ishikawa T. Structure of dimericaxonemal dynein in cilia suggests an alternative mechanism of force generation. Cytoskeleton (Hoboken). 2014;71:412–22. 20. Ishikawa T.  Structural biology of cytoplasmic and axonemaldyneins. J Struct Biol. 2012;179:229–34. 21. Chilvers MA, O'Callaghan C.  Analysis of ciliary beat pattern and beat frequency using digital high speed imaging: comparison with the photomultiplier and photodiode methods. Thorax. 2000;55:314–7. 22. Antunes MB, Cohen NA. Respiratory cilia: Mucociliary clearance. In: Stucker FJ, Souza CD, Kenyon GS, Lian TS, Draf W, Schick B, editors. Rhinology and facial plastic surgery. New York: Springer; 2009. 23. Gueron S, Levit-Gurevich K, Liron N, Blum JJ.  Cilia internal mechanism and metachronal coordination as the result of hydrodynamical coupling. Proc Natl Acad Sci U S A. 1997;94:6001–6. 24. Teff Z, Priel Z, Gheber LA. The forces applied by cilia depend linearly on their frequency due to constant geometry of the effective stroke. Biophys J. 2008;94:298–305. 25. Satir P. The role of axonemal components in ciliary motility. Comp Biochem Physiol A Comp Physiol. 1989;94:351–7. 26. Keeling J, Tsiokas L, Maskey D.  Cellular mechanisms of ciliary length control cells. 2016; 5(1): pii: E6. 27. Messerklinger W.  On the drainage of the normal frontal sinus of man. Acta Otolaryngol. 1967;63:176–81. 28. Brokaw CJ. Control of flagellar bending: a new agenda based on dynein diversity. Cell Motil Cytoskeleton. 1994;28:199–204. 29. Satir P, Christensen ST.  Overview of structure and function of mammalian cilia. Annu Rev Physiol. 2007;69:377–400. 30. Yeh TH, Su MC, Hsu CJ, Chen YH, Lee SY.  Epithelial cells of nasal mucosa express functional gap junctions of connexin 43. Acta Otolaryngol. 2003;123:314–20. 31. Gheber L, Priel Z. Synchronization between beating cilia. Biophys J. 1989;55:183–91. 32. Sutto Z, Conner GE, Salathe M. Regulation of human airway ciliary beat frequency by intracellular pH. J Physiol. 2004;560:519–32. 33. Green A, Smallman LA, Logan AC, Drake-Lee AB. The effect of temperature on nasalciliary beat frequency. Clin Otolaryngol Allied Sci. 1995;20:178–80. 34. Wong LB, Miller IF, Yeates DB. Stimulation of ciliary beat frequency by autonomic agonists: in vivo. J Appl Physiol. 1988;65:971–81. 35. Sanderson MJ, Dirksen ER.  Mechanosensitivity of cultured ciliated cells from the mammalian respiratory tract: implications for

69 the regulation of mucociliary transport. Proc Natl Acad Sci U S A. 1986;83:7302–6. 36. Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest. 2002;109:571–7. 37. Tarran R, Trout L, Donaldson SH, Boucher RC.  Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. J Gen Physiol. 2006;127:591–604. 38. Lai SK, Wang YY, Wirtz D, Hanes J. Micro- and macrorheology of mucus. Adv Drug Deliv Rev. 2009;61:86–100. 39. King M.  Physiology of mucus clearance. Paediatr Respir Rev. 2006;7:S212–4. 40. Vallet C, Escudier E, Roudot-Thoraval F, Blanchon S, Fauroux B, Beydon N, et  al. Primary ciliary dyskinesia presentation in 60 children according to ciliary ultrastructure. Eur J Pediatr. 2013;172:1053–60. 41. Zariwala MA, Omran H, Ferkol TW. The emerging genetics of primary ciliary dyskinesia. Proc Am Thorac Soc. 2011;8:430–3. 42. Haq IJ, Gray MA, Garnett JP, Ward C, Brodlie M. Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets. Thorax. 2016;71:284–7. 43. Uslu H, Uslu C, Varoglu E, Demirci M, Seven B. Effects of septoplasty and septal deviation on nasal mucociliary clearance. Int J Clin Pract. 2004;58:1108–11. 44. Ulusoy B, Arbag H, Sari O, Yöndemli F. Evaluation of the effects of nasal septal deviation and its surgery on nasal mucociliary clearance in both nasal cavities. Am J Rhinol. 2007;21:180–3. 45. Soane RJ, Carney AS, Jones NS, Frier M, Perkins AC, Davis SS, Illum L.  The effect of the nasal cycle on mucociliary clearance. Clin Otolaryngol Allied Sci. 2001;26:9–15. 46. Passali D, Bellussi L, Lauriello M.  Diurnal activity of the nasal mucosa. Relationship between mucociliary transport and local production of secretory immunoglobulins. Acta Otolaryngol. 1990;110:437–42. 47. Cohen NA. Sinonasalmucociliary clearance in health and disease. Ann Otol Rhinol Laryngol Suppl. 2006;196:20–6. 48. Stevens WW, Lee RJ, Schleimer RP, Cohen NA.  Chronic rhinosinusitis pathogenesis. J Allergy Clin Immunol. 2015;136: 1442–53. 49. Sun SS, Hsieh JF, Tsai SC, Ho YJ, Kao CH. The role of rhinoscintigraphy in the evaluation of nasal mucociliary clearance function in patients with sinusitis. Nucl Med Commun. 2000;21:1029–32. 50. Sun SS, Hsieh JF, Tsai SC, Ho YJ, Kao CH.  Evaluation of nasal mucociliary clearance function in allergic rhinitis patients with technetium 99m-labeled macroaggregated albumin rhinoscintigraphy. Ann Otol Rhinol Laryngol. 2002;111:77–9. 51. Kirtsreesakul V, Somjareonwattana P, Ruttanaphol S. The correlation between nasal symptom and mucociliary clearance in allergic rhinitis. Laryngoscope. 2009;119:1458–62. 52. Randell SH, Boucher RC; University of North Carolina Virtual Lung Group Effective mucus clearance is essential for respiratory health. Am J Respir Cell Mol Biol 2006; 35:20–28. 53. Stannard W, O'Callaghan C. Ciliary function and the role of cilia in clearance. J Aerosol Med. 2006;19:110–5. 54. Corbo GM, Foresi A, Bonfitto P, Mugnano A, Agabiti N, Cole PJ.  Measurement of nasalmucociliary clearance. Arch Dis Child. 1989;64:546–50. 55. Andersen I, Lundqvist GR, Proctor DF.  Human nasal mucosal. Arch Environ Health. 1971;23:408–20. 56. Deitmer T. A modification of the saccharine test for nasal mucociliaryclearance. Rhinology. 1986;24:237–40. 57. Dostbil Z, Polat C, Uysal IÖ, Bakır S, Karakuş A, Altındağ S.  Evaluation of nasal Mucociliary transport rate by Tc-macroaggregated albumin Rhinoscintigraphy in woodworkers. Int J Mol Imaging. 2011:620482.

70 58. De Boeck K, Proesmans M, Mortelmans L, Van Billoen B, Willems T, Jorissen M. Mucociliary transport using 99mTc-albumin colloid: a reliable screening test for primary ciliary dyskinesia. Thorax. 2005;60:414–7. 59. Rizzo JA, Medeiros D, Silva AR, Sarinho E. Benzalkonium chloride and nasal mucociliary clearance: a randomized, placebo-­controlled, crossover, double-blind trial. Am J Rhinol. 2006;20:243–7. 60. Dostbil Z, Dag Y, Cetinkaya O, Akdag M, Tasdemir B. Assessment of technetium-99m labeled macroaggregated albumin rhinoscintigraphy for the measurement of nasal mucociliary transport rate: intratest, interobserver, and intraobserver reproducibility. Scientifica (Cairo) 2014: 982515, 2014, 1. 61. Di Giuda D, Galli J, Calcagni ML, Corina L, Paludetti G, Ottaviani F, De Rossi G. Rhinoscintigraphy: a simple radioisotope technique to study the mucociliary system. Clin Nucl Med. 2000;25:127–30. 62. Chilvers MA, Rutman A, O'Callaghan C.  Ciliary beat pattern is associated with specific ultrastructural defects in primary ciliary dyskinesia. J Allergy Clin Immunol. 2003;112:518–24. 63. Schipor I, Palmer JN, Cohen AS, Cohen NA.  Quantification of ciliary beat frequency in sinonasal epithelial cells using differential interference contrast microscopy and high-speed digital video imaging. Am J Rhinol. 2006;20:124–7.

D. T. Edizer et al. 64. Clare DK, Magescas J, Piolot T, Dumoux M, Vesque C, Pichard E, et al. Basal foot MTOC organizes pillar MTs required for coordination of beating cilia. Nat Commun. 2014;12(5):4888. 65. Gamarra F, Bergner A, Stauss E, Stocker I, Grundler S, Huber RM.  Rotation frequency of human bronchial and nasal epithelial spheroids as an indicator of mucociliary function. Respiration. 2006;73:664–72. 66. Tsang KW, Tipoe GL, Mak JC, Sun J, Wong M, Leung R, et  al. Ciliary central microtubular orientation is of no clinical significance in bronchiectasis. Respir Med. 2005;99:290–7. 67. O'Brien DW, Morris MI, Ding J, Zayas JG, Tai S, King M. A mechanism of airway injury in an epithelial model of mucociliary clearance. Respir Res. 2004;5:10. 68. Zayas JG, O'Brien DW, Tai S, Ding J, Lim L, King M. Adaptation of an amphibian mucociliary clearance model to evaluate early effects of tobacco smoke exposure. Respir Res. 2004;5(9) 69. Macchione M, Lorenzi-Filho G, Guimarães ET, Junqueira VB, Saldiva PH.  The use of the frog palate preparation to assess the effects of oxidants on ciliated epithelium. Free Radic Biol Med. 1998;24:714–21.

8

Olfactory Function Nihat Susaman, Aytuğ Altundağ, and Philippe Rombaux

8.1

Introduction

The sense of smell is one of the earliest sensory systems to have evolved in mammals, as can be seen from phylogenetic studies. It is a chemical recognition system that has an influence on food-related behaviour, social and sexual function. Amongst neurones, the only group possessing regenerative abilities are the highly differentiated olfactory epithelial cells. The olfactory system comes into operation whenever odoriferous compounds come into contact with the olfactory vesicles, as they are known [1, 2]. Air is directed upwards towards the olfactory epithelium by the nasal turbinates (conchae). This epithelium is located within the superior and posterior portion of the cavity of the nose. Whilst a mere 2  cm in extent, this area houses more than 100 million olfactory receptor cells (ORCs). The epithelial cells responsible bear a specialised structure, the olfactory vesicle, with kinocilia, and this is where the stimulus is first transduced into an electrical impulse. Compared with other mammals, such as rodents, the human olfactory system is less highly evolved [1].

8.2

Anatomy of the Olfactory System

8.2.1 Olfactory Epithelium There are three cell populations represented within the olfactory epithelium: basal, supporting cells, and olfactory receptor cells. Basal cells differentiate into ORCs. The fact that N. Susaman (*) Department of Otorhinolaryngology, University of Health Sciences, Elazığ Training and Research Hospital, Elazıg, Turkey A. Altundağ Istanbul Smell and Taste Center, Istanbul, Turkey

these cells continue to differentiate into neurones and be turned over is a unique feature of the olfactory system. Indeed, there is no other comparable population of cells in the entire mature central nervous system (CNS). Support cells have numerous microvilli and contain granules for secretion. They are interspersed amongst ORCs, and secrete granular contents over the mucosal surface [1, 2]. ORCs are, morphologically, bipolar neurons. They have a slender dendritic process consisting of specialised cilia that project out of the olfactory vesicle, and a long axonic process that contributes to the filia olfactoria. The cilia provide a vast surface area on which odour-bearing molecules can act [1]. Typically, some cilia (around 6–8) are not fully formed and lack motility. The vomeronasal organ is a specialised structure found bilaterally, composed of membranes, and located basally within the anterior septum of the nose, at the point of intersection of the cartilage and bone. It is believed that this structure can identify special signals termed pheromones, which operate in humans at a subconscious level to cause changes in the endocrine and autonomic nervous system and effect alterations in the psychological state. There is a projection of Cranial Nerve V to the posterior part of the nasal cavity, which provides noxiception [1]. It is widely thought that only a minority of normal individuals possesses the vomeronasal organ, and it has no function usually. The olfactory epithelium is distributed over the nasal roof, upper end of the septum, and the superior conchae. Also, present within the mucosa are Bowman’s glands. The ORCs are considered to be protoneurones [3]. As described earlier, their morphology is bipolar, with the dendritic portion extending to the epithelial free surface, and the axons bundled into filia olfactoria. The filia are unsheathed. From the filia, which are about 20 on each side, there arise the paired first cranial nerves, which transit through the formina of the cribriform plate [4].

P. Rombaux Department of Otorhinolaryngology, Saint-Luc University, Brussels, Belgium e-mail: [email protected] © Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_8

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8.2.2 O  lfactory Nerve and the Cribriform Plate The unmyelinated ORC axons combine to produce the slender olfactory nerves, passing internally to the olfactory bulb on the same side, where they make a synaptic connection with second-order neurones. The conduction is surprisingly slow, and a lone Schwann cell layer provides support. The trigeminal nerve has projections that identify caustic molecules, such as ammonia [1]. The cribriform plate has many openings, the foramina, through which the fila olfactoria pass. It is divided centrally by the crista galli. If the plate is fractured traumatically, these fibres are vulnerable to damage resulting in olfactory dysfunction [1].

8.2.3 Olfactory Bulbs and Tract The olfactory bulb is located basally to the frontal lobe. It has a highly organised structure comprising several distinct layers with different synaptic connections. Moving inwards, these are the layers of the bulb [1]: • • • • •

Glomerular. External plexiform. Mitral cell. Internal plexiform. Granule cell.

Mitral cells synapse with olfactory nerve axons within the globular layer. Mitral cells, thus, act as second-order neurones. The glomerular layer includes olfactory nerve fibres, the multiple branching dendrites of mitral cells (known as glomeruli), and the periglomerular cells, which themselves synapse with multiple dendritic extensions of the mitral cells. The net effect of these is to inhibit the laterally adjacent glomeruli, whilst selectively exciting specific mitral cell glomeruli. A single mitral cell may synapse with over 1000 olfactory axons [1]. Within the external plexiform layer, there are mitral cell axons passing through the layer, and tufted cells, which are the same size as the mitral cells. The granular cells of the granular cell layer form dendrodendritic synapses, a specialised type of synapse which features vesicles both pre- and postsynaptically, and is known as a reciprocal synapse [1]. Tufted cells similarly form both dendrodendritic and dendrosomatic connections with granule cells. Between the external and internal plexiform layers is a thin band of mitral cells of a pyramidal type. These cells are the largest neurones in the olfactory bulbs [1].

Within the granular layer are some non-axon-bearing neurone-type cells of circular morphology. They have extensive dendrites which synapse with both mitral cells and the tufted cells. They form synapses, via short dendrites, with the axons of mitral cells leaving the bulb [1]. Thus, the olfactory nerves connect with the olfactory bulbs, which are ovoid and lie atop the cribriform plate. The bulbs are a part of the central nervous system with second-­ order neurones of bipolar morphology, referred to as mitral cells. Their development occurs within the olfactory tract beneath the cortical olfactory sulcus, in the space between the right gyrus and the medial orbital gyrus [5].

8.2.4 T  he Olfactory Cortical and Subcortical Areas The olfactory tract divides into the lateral stria, medial stria, and intermediate stria just anterior to the anterior perforated substance [5].

8.2.4.1 The Medial Stria [6] The medial strial fibres synapse in the septal nuclei of the subcallosal region, whence two bundles continue: the stria medullaris, projecting to the nuclei of the habenula, together with the reticular formation, salivary nuclei and nucleus dorsalis of the vagal nerve; and the olfacto-hypothalamo-­ tegmental bundle [7]. By appreciating how the septal area and brain stem form a circuit via the habenula and the hypothalamus, we can make sense of the way smells, whether appetising or disgusting, can lead to salivation or nausea and cause peristaltic variations within the gut [4]. 8.2.4.2 The Lateral Stria [6] The lateral striae project to the medial aspect of the temporal lobe, encountering (in order of posterior progression) the pre-piriform cortex, the pre-amygdalic cortex, the uncus, and ultimately the parahippocampal cortex, covering which is entorhinal cortex. The parahippocampal cortical region is in communication with the hypothalamus, and more distantly with the thalamic mediodorsal nucleus, the orbitofrontal cortical region, and the insula. The connections explain the way smells are remembered, characterized, and can have effects on wide-ranging aspects of behaviour, from the food we enjoy, to sexual behaviour, and even to the way mothers and children bond [4]. 8.2.4.3 The Intermediate Stria [5] These fibres pass towards structures which have given way in phylogenesis to the anterior perforated substance [5].

8  Olfactory Function

8.3

General Physiology of Olfaction

The sense of smell is fundamental for both humans and other animals. Indeed, from an evolutionary perspective, olfaction may be one of the first senses to have developed. This sense plays a role in recognition of food, mate selection, predator avoidance, and can both give joy from pleasant sensations (such as floral perfumes) and warning of lurking dangers (rotten food). Olfaction is an integral part of environmental interaction for both humans and other animals [8]. Odorants are volatile chemical compounds which are wafted towards the olfactory cleft by the mechanics of taking a breath. The olfactory apparatus in humans is situated bilaterally in the nasal cavity roof, in an inferomedial direction from the orbit [9]. For a compound to elicit an olfactory response, it needs to possess certain characteristics: it requires both hydrophilic and lipophilic properties, must be volatile, non-polar, and have chemical activity on its outer surface. Up to now, no molecule above 294 Daltons molecular weight has been found capable of eliciting an olfactory response [9]. There is, in effect, no limit on the number of different odours which may be distinguished from each other by the olfactory system, and the concentrations at which olfaction is possible are surprisingly dilute [10]. Each side of the nose has a mere 2.5 cm2 of olfactory epithelium, into which some 50 million ORCs in total are crowded [8]. Within the olfactory area, the cilia project downwards towards the lumen into the mucus layer, which are around 60 μ in depth. The mucus is composed of a lipid-rich secreted liquid which acts to clean the receptors on the external surface of the ORCs. The mucus comes from Bowman’s glands located within the epithelial layer. Lipids play an essential role in the mucous functions as any compound that is to produce an olfactory response must first dissolve in the mucus before they can reach the cilia of the ORCs and act on receptors there. ORCs possess between 8 and 20 cilia, whip-like extensions which are 30–200 μ in length. Odoriferous molecules are bound to the cilia and electrical transduction begins within the ORC [8]. Deep to the surface of the mucosa is the basal layer of the olfactory epithelium, composed in part of basal cells capable of mitotic division to produce the progenitors of ORCs, which then mature within the epithelium to produce ORCs themselves. ORCs have a lifetime of approximately 40 days. There are also cells within the epithelium that have a yellowish hue that seems to correlate with the ability to smell [8]. In another mammal, the dog, they are dark yellow to brown in colour.

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One pole of the ORCs is in contact with the external environment, where they interact with odours, whilst the other pole is a long axon that joins other axons below the epithelium and travels in groups of 10–100 axons via the ethmoidal cribriform plate to the olfactory bulbs. Within the bulbs, they synapse at the glomeruli, which in turn synapse with mitral cells. For comparison, a rabbit has 26,000 ORCs synapsing within 200 glomeruli, after which 25 such glomeruli make a synaptic connection with each mitral cell. Thus, around 1000 ORCs provide input on average to each mitral cell [8]. This arrangement acts physiologically to heighten the sensitivity of the olfactory system and its ability to transduce chemical signals to the brain. Thus, olfactory sensory information is funnelled through the olfactory nerves to the mitral cells and thence to the corticomedial amygdala, where the processing of the incoming signals takes place and responses originate [8].

8.4

 he Trigeminal Sense in the Olfactory T Epithelium

It is worthy of note that the olfactory epithelium contains within it a further sensory system—the trigeminal nerve receptors. In Man, the olfactory system per se is limited in extent, but the trigeminal nerve is the largest of the cranial nerves, and has numerous projections: sensory to the face, teeth, oral cavity, and most of the scalp; motor to the muscles of mastication; and further sensory input in the form of tactile, baroceptive, nociceptive, and temperature sensitive inputs around the eyes, periorally, and nasally. There are multiple substances capable of exciting the sensation of heat or cold, tingling or irritation via the trigeminal innervation. (Levo-)menthol in mid concentrations excites the feeling of coolness, whilst a higher concentration is perceived as heat within the nose. In fact, this sensory perception is not confined to the nose, oral cavity, or eyes, but instead can be generated on skin regions without trigeminal innervation such as the genitals. We can conclude from this that such perceptions originate from a variety of nervous receptors. Camphor, which is much more aromatic even than menthol, likewise produces the perception of cold via the trigeminal sense. Ohloff concludes that approximately 70% of odoriferous compounds can stimulate the trigeminal, although it is usual for the trigeminal sensitivity to be much lower than that of the olfactory system proper [10]. Some other compounds with a commonly occurring effect on the trigeminal are allyl isothiocyanate (found in mustard and mustard oil), capsaicin (an ingredient of hot chilli powder and mace spray), and diallyl sulfide (produced by onions) [8].

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References 1. VokshoorA. Olfactory system anatomy. In: MeyersAD (Ed.). Medscape. http://emedicine.medscape.com/article/835585-overview# showall. Accessed 11 Dec 2015. 2. Díaz D, Gómez C, Muñoz-Castañeda R, Baltanás F, Alonso JR, Weruaga E.  The olfactory system as a puzzle: playing with its pieces. Anat Rec (Hoboken). 2013;296(9): 1383–400. 3. Sanders RD, Gillig PM.  Cranial nerve I.  Psychiatry. 2009;6(7): 30–5. 4. Leboucq N, Menjot de Champfleur N, Menjot de Champfleur S, Bonafé A.  The olfactory system. Diagn Interv Imaging. 2013;94(10):985–91. https://doi.org/10.1016/j.diii.2013.06.006. Epub 2013 Aug 7.

N. Susaman et al. 5. Delmas A. Les voies olfactives et le lobe olfactif: paléocortex. In: Masson, editor. Voies et centres nerveux. 10e ed. Paris: Masson; 1981. p. 218—20. 6. Kahle W.  Paleocortex. In: Cabrol C, editor. Anatomie 3 système nerveux. 2e ed. Paris: Flammarion-Médecine-sciences; 1990. p. 210. 7. Duus P. Le nerf olfactif. In: Von Hassler R, editor. Diagnostic neurologique les bases anatomiques. 6 ed. Paris-Bruxelles: De Boeck Université; 1998. p. 109—11. 8. Leffingwell JC.  Olfaction. Leffingwell & Associates. http://www. leffingwell.com/olfaction.htm. Accessed 11 Dec 2015. 9. Demole E, Wuest H. Synthèses stéréosélectives de deux trioxydes C18H30O3 stéréoisomères, d’ambréinolide et sclaréol-lactone a partir de derives du (+)-manool. Helv Chem Acta. 1967;50:1314. 10. Ohloff G. Scent and fragrances. Berlin: Springer; 1994.

9

Application of Computational Fluid Dynamics Methods to Understand Nasal Cavity Flows Andreas Lintermann

In recent years, computational fluid dynamics (CFD) methods have become a valuable tool to analyze the intricate flow in the human nasal cavity. Early studies addressed the flow in artificial models of the nasal cavity [1–5]. The availability of high-resolution computed tomography (CT) or magnetic resonance tomography (MRT) data and the corresponding software to pre-process medical images enabled, however, to investigate realistic and individual nasal cavity geometries by means of numerical simulations [6–20]. To exploit the capabilities of CFD methods to predict nasal cavity flows, an overview of different approaches that are frequently used in the field of respiratory-related bio-fluid mechanics is given in this chapter. In more detail, Sect. 9.1 presents a general approach to pre-process medical data for flow simulations. Subsequently, meshing methods for space discretization are discussed in Sect. 9.2 before an overview of different simulation methods is given in Sect. 9.3. In Sect. 9.4, tools for the analysis of the flow in the human nasal cavity as computed by CFD methods are discussed and finally, in Sect. 9.5, potentials to use such methods in clinical applications are highlighted.

by (semi-)automatic segmentation tools. The segmentation method basically depends on the quality and type of the available image data. That is, in case of MRT data, tissue and air is often difficult to distinguish and the resolution is often quite low. Hence, experienced personnel need to identify the volume of interest, i.e., the air volume within the nasal cavity. In contrast, CT images feature hard interfaces between air and tissue. They can be identified by strong gradients in the Hounsfield data by automatic segmentation algorithms. From the extracted air volume, nasal cavity surfaces are generated via a 3D reconstruction algorithm [22]. The resulting surfaces are discrete approximations to the real nasal cavity and often require to apply non-shrinking smoothing algorithms [23] to remove stair-step artifacts originating from the discrete voxel-structure of the medical images. In the end of this pre-processing step, such surfaces are often given by a collection of triangles that in sum define a watertight two-­ manifold surface. Tools that are frequently used for pre-­ processing are, amongst others, 3D Slicer1 [24], the Medical Imaging Interaction Toolkit (MITK)2 [25], OsiriX3 [26], or software packages from Materialise.4

9.1

9.2

 re-Processing Medical Image Data P for the Use in Numerical Simulations

The preparation of medical image data for CFD-based analyses usually follows a certain pipeline [15, 21]. Starting from the acquired CT or MRT data, the surface of the nasal cavity is extracted from these images either by the support of radiologists and ENT specialists using manual segmentation or A. Lintermann (*) Institute of Aerodynamics and Chair of Fluid Mechanics, RWTH Aachen University, Aachen, Germany Simulation Laboratory Highly Scalable Fluids and Solids Engineering, Jülich Aachen Research Alliance Center for Simulation and Data Science (JARA-CSD), RWTH Aachen University, Aachen, Germany e-mail: [email protected]

Space-Discretization through Meshing

The equations describing the physics of fluid flow, which are solved in numerical simulations are either given in integral or in partial derivative form. Computers, however, require the equations to be in their discrete formulation, i.e., integrals and derivatives need to be approximated by their according discrete form. To account for the discretization of the equations and to find numerical solutions, the space is split into small discrete volumes. This procedure is called 3D Slicer https://www.slicer.org MITK http://mitk.org 3  OsiriX http://osirix-viewer.com 4  Materialise http://biomedical.materialise.com 1  2 

© Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_9

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meshing or grid generation and delivers the volume of interest partitioned into small volumetric elements, which in sum constitute the computational grid. Depending on the simulation method, such grids may consist of a collection of tetrahedrals or prisms, a combination of both that smoothly adapt to the surface of the nasal cavity, or of a collection of cubes that may stick out of the surface and that require a second pre-processing before a simulation can be run. The discrete elements are also referred to as computational cells and will in the simulation contain information on the flow such as the pressure, temperature, velocity, or density. Computational meshes can be structured or unstructured. That is, structured meshes allow for a continuous cell indexing (i, j, k) for all three space dimensions, where the neighborhood of a cell is uniquely identifiable by (i ± 1, j ± 1, k ± 1). Simulation codes using structured meshes are in general fast due to aligned memory access, however, necessitate to construct the meshes manually for complex shapes. This makes them rather unsuitable for the simulation of nasal cavity flows. In contrast, memory access in unstructured meshes like tetrahedral, hybrid tetrahedral/prism, and Cartesian meshes (cube meshes) is less efficient due to the non-continuous indexing. However, such meshes can be constructed fully automatically, especially the generation of hierarchical Cartesian meshes that define in 3D an octree structure by parent–child relationships between coarse cells and finer cells can be implemented very efficiently [27]. The parent-child relationship in such meshes is obatined by continous subdivision of the cells in the octree. In all meshing cases, the volume or the spatial distance of these cells defines the resolution of the mesh and hence it also determines the quality of the simulation output. While laminar flow requires in general low resolutions, high Reynolds-number flows, i.e., cases where the inertial forces are way bigger than the viscous forces, transitional and turbulent flow appears, and high gradients of the flow variables are expected, high mesh resolutions are required to resolve all flow features. Mathematically, the Reynolds number is defined by Re = u · D/𝑣, where u is a reference velocity, D is some characteristic length, and 𝑣 is the kinematic viscosity of the fluid. Furthermore, the force acting on the tissue in addition to the pressure, namely, the wall-shear stress, is frequently of interest. Its computation requires an accurate evaluation of the velocity gradient close to the wall. Therefore, the boundary layer, whose thickness is a function of the Reynolds number, needs to be resolved by refined meshes close to the wall to obtain an accurate representation of the gradient. Examples of different mesh types are depicted in Fig. 9.1 To show that the resolution of a mesh is sufficient, so-­ called grid dependence studies are usually performed. Therefore, the same simulation is run at different resolutions and the results are juxtaped. That is, the best resolution is determined, e.g., by comparing local flow profiles, general

A. Lintermann

properties such as the pressure loss along a nasal cavity or the corresponding heating capability, by analyzing the accuracy of wall-shear stress computations or the flow field energy spectra. Latter delivers information on the range of structures that can be captured with a given resolution. Meshing tools can be categorized in commercially available, open source tools, and in-house methods. Some frequently used commercial tools are ANSYS ICEM CFD,5 ANSYS Meshing,6 PointwiseGridgen,7 or SALOME,8 which may provide various mesh types. Furthermore, the mesher in OpenFOAM,9 snappyHexMesh,10 and NETGEN11 are freely available. In-house flow solvers sometimes also use their own meshing tools [27] that are suited for specific classes of problems and solution methods, allow for an automatization of the grid generation process, and are highly flexible when it comes to meshing of complex geometries.

9.3

 umerical Approaches to Solve the N Governing Equations of Fluid Mechanics

In CFD simulations, the fundamental equations of motion, i.e., the conservation of mass, momentum, and energy (the Navier–Stokes equations) can be solved by numerous numerical schemes. Among the most popular ones are the finite volume (FV), finite element (FE), finite difference (FD), discontinuous Galerkin (DG), and the lattice-­ Boltzmann (LB) methods. Different sets of equations may be solved in this context, however, all of them can be derived from the Navier–Stokes equations. To be more specific, the Reynolds-averaged Navier–Stokes (RANS) equations, the Navier–Stokes equations with or without small-scale modeling approaches, or the Boltzmann equation are solved. Simulations solving the RANS equations are mainly suited for high-Reynolds-number flows. In this approach, the temporally averaged equations are solved and the flow is split into a mean and a fluctuating part. The derivation of the RANS equations leads to a new term, i.e., the Reynolds stresses that are required to be approximated by turbulence models. One can imagine this kind of method as running an under-resolved simulation delivering a mean flow and adding a model representing the energy transfer between small-­ ANSYS ICEM CFD http://resource.ansys.com/Products/Other+ Products/ANSYS+ICEM+CFD 6   ANSYS Meshing http://www.ansys.com/Products/Platform/ ANSYS-Meshing 7  PointwiseGridgen http://www.pointwise.com/pw 8  SALOME http://www.salome-platform.org 9  OpenFOAM http://www.openfoam.com 10  snappyHexMesh https://github.com/nogenmyr/swiftSnap 11  NETGEN http://www.hpfem.jku.at/netgen/ 5  

9  Application of Computational Fluid Dynamics Methods to Understand Nasal Cavity Flows

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Fig. 9.1  Examples of different computational meshes used for CFD simulations in the human respiratory tract. (a) Cartesian mesh as constructed by a parallel grid generator [27]. (b) Manually generated block-structured mesh [2]. (c) Mixed tetrahedra/prism mesh

Prism layers

Tetrahedral mesh

Pharynx

scale and continuously decaying structures. The approximations that are frequently used in RANS computations, e.g., the two equation-models k-𝜀 [28] or k-ω [29], which deliver additional equations for the turbulent kinetic energy k and the dissipation 𝜀 or the vorticity ω, are derived for cases that have little in common with the intricate flow in the human respiratory tract. Furthermore, these models require empirical constants that need to be specifically tuned for the individual simulation case. Despite these drawbacks, RANS computations are often used in the community and in industry due to their attractive low computational costs. Another approach is running a large-eddy simulation (LES), which solves the spatially filtered Navier–Stokes equations and models the filtered parts by so-called sub-grid scale models. That is, models mimic the filtered fine-scale structures. LES computations allow for the simulation of temporally resolved flow fields that cover a larger range of turbulent structures than those covered by RANS computations. The method that does not model any scales at all is called a direct numerical simulation (DNS) in which the full Navier–Stokes equations are solved directly. DNS are the most expensive simulations. In contrast to RANS or LES computations they allow, however, for a fully detailed analysis of complex fluid flows. FV methods solve the Navier–Stokes equations in their integral formulation, while FD methods use the partial differential formulation. FE methods and DG methods alike solve the problem by considering weak formulations of the

Navier-Stokes equations. The LB method differs from all of the aforementioned approaches as it solves the discrete Boltzmann equation that describes the fate of gas particles by probability distribution functions and hence by statistical means. In LB methods, the macroscopic variables such as pressure, temperature, velocity, or density, can simply be obtained from the moments of these probability distribution functions, while in the other methods these variables are direct results of a simulation or need to be computed in addition. For example, in incompressible flows it is often required to solve the pressure-Poisson equation to obtain the pressure. Using these different methods, also the time is discretized. Marching foward in time, the next time step is either only dependent on the previous time step (explicit schemes) or on the previous and current time step (implicit schemes). In general, implicit schemes require to solve a huge linear system of equations and the time step is variable, while in explicit schemes the time step is fixed and the new state of the flow field can simply be determined from the last solution step. The interested reader is referred to [30] for FD and FV methods. A detailed description of LB methods can be found in [31] and the DG method is described in [32]. As previously mentioned, RANS computations are rather inexpensive and can be run in a short amount of time on smaller desktop machines. Unlike RANS simulations, LES and DNS computations require high processing power and a higher amount of available memory, i.e., desktop machines are too small to solve these problems in a reasonable amount

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of time. That is, such computations can only be performed on high-performance computers (HPC) that, nowadays in the petascale era, consist of hundreds of thousands of processing cores, each equipped with a certain amount of memory that sums up to several terabytes for the whole machine. For the simulation, the problem is distributed among the available processors such that each processor simulates only a small fraction of the whole problem. Obviously, each processor cannot solve the problem independently and hence information needs to be exchanged among the processors. This is realized by performing communication over the network across computational nodes. Fortunately, HPC networks are designed for high communication throughput. On node-­ level, information exchange is either implemented by shared memory access or by direct communication between the participating CPU cores. Although current HPC systems use high-bandwidth and low-latency networks, indeed communication is one of the major issues that slows down simulation software and limits scaling across an extremely large number of computational cores. Algorithmic and hardware performance is hence an active field of research that guides software and HPC into the next generation supercomputing era (exascale era). Note that current HPC systems are mainly available for research institutes conducting large-scale simulations, however, as time evolves and computing power becomes more and more affordable, it will be possible to run LES computations on local cluster systems in the near future. Software that is frequently employed for the simulation of flows are either commercial tools like ANSYS Fluent,12 ANSYS CFX,13 CD-adapco products (STAR-CD,14 STAR-­ CCM+15), EXA PowerFLOW,16 open source codes like OpenFOAM, OpenLB,17 Code Saturne,18 or in-house codes like ZFS19and Alya,20 developed at the Institute of Aerodynamics and Chair of Fluid Mechanics, RWTH Aachen University, and the Barcelona Supercomputing Center, respectively. All of the aforementioned methods find application in the simulation of nasal cavity flows and have their advantages and disadvantages. However, to not distract the reader from the real problem, i.e., the simulation of nasal cavity flows, in

ANSYS Fluent http://www.ansys.com/Products/Fluids/ ANSYS-Fluent 13   ANSYS CFX http://www.ansys.com/Products/Fluids/ANSYS-CFX 14  CD-adapco STAR-CD http://www.cd-adapco.com/products/star-cd 15  CD-adapco STAR-CCM+ http://www.cd-adapco.com/products/ star-ccm 16   EXA PowerFLOW  http://exa.com/product/simulation-tools/ powerflow-cfd-simulation 17  OpenLB http://optilb.org/openlb 18  Code Saturne http://code-saturne.org 19  ZFS http://www.aia.rwth-aachen.de 20  Alya http://www.bsc.es/es/computer-applications/alya-system 12  

A. Lintermann

the next section the focus is rather on the tools to analyze and understand the physics of the flow than on the applied method.

9.4

 FD Computations of the Flow in the C Human Nasal Cavity

The most important aspect that determines the comfort of a patient is how easy it is to breathe. Swollen turbinates, perforated or bend septa lead to a reduced breathing capability, make respiration strenuous, and hence reduce the comfort of a patient. Considering inspiration, the facility to breath can simply be characterized by the amount of energy that is lost in the respiration process, i.e., the higher the energy loss the more difficult it is to inhalte. As already stated in Sect. 9.2, the energy required to inhale can be described by considering the pressure loss, i.e., by considering Bernoulli’s equation [33]. However, one needs to take care that Bernoulli’s equation is only valid along a streamline in steady, incompressible, and inviscid flow and that the outcome of such an analysis is hence only an approximation to the real pressure loss. Furthermore, it is important to note that Bernoulli’s equation considers the total pressure, which consists of the static pressure and the dynamic pressure. Latter is basically the kinetic energy contribution of the moving fluid. This is unfortunately often omitted when analyzing the flow and only the static pressure difference is assumed to represent the pressure loss. Despite the fact that the share of the dynamic pressure is in general small, locally it may vary extremely due to fluid accelerations. For example, consider a flow without losses that passes an orifice, say an airway restriction in the nasal cavity. Then, Bernoulli’s equation states that the total pressure is the same at the entry of the diverging part as at the orifice. Since the velocity increases due to the channel divergence, the dynamic pressure increases as well. This goes along with a decrease of the static pressure leading to the same values of the total pressure at both locations at the end. Streamlines in transient or quasi-steady simulations may rapidly change their course and are hence not very suited for the pressure loss evaluation. Hence, it either makes sense to consider the area-averaged total pressure difference of the nostrils and the pharynx or to place streamlines into the flow field that pass the regions to analyze and are based on time-averaged solutions. This is for example done in [9, 15, 34]. This way, one can obtain an integral pressure or energy loss using former method while with the latter localized information can be obtained that takes into account the local static and dynamic pressure. Plotting the accumulated loss along a streamline then delivers an idea where most of the energy is lost. An example of a streamline extracted from an averaged flow field is shown in Fig. 9.2a. The plot ∆pt,l(Nm,s) in Figure 9.2b shows the accumulated total pressure loss along this

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9  Application of Computational Fluid Dynamics Methods to Understand Nasal Cavity Flows Fig. 9.2  Analysis of the total pressure loss along streamlines in three different nasal cavities on the left side (subscript ‘l’, patient view) as prformed in [15]. Note that Δpt is in its non-dimensional form and that the arc length s has been normalized to 1 with the total arc length of the streamline st. (a) Surface of one of the nasal cavities and a streamline for which in (b) the according accumulated pressure loss is shown. (b) Accumulated total pressure loss along streamlines in three different nasal cavities. The plot for Nm corresponds to the cavity shown in (a)

a

b

1.8

∆pt,l(Ng,s)

1.6

∆pt,l(Nm,s) ∆pt,l(Np,s)

1.4

∆pt

1.2 1 0.8 0.6 0.4 0.2 0

1

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streamline. Prominent locations for increased pressure loss are airway restrictions as they appear in the nasal valve or in swollen turbinates. Strong shear stress acting on the fluid that appears, e.g., in regions with high velocity gradients in wallnormal direction, at sharp corners, which may lead to flow separation, or in higher Reynolds number flows, are also important factors radically influencing the energy loss. It is hence not surprising that the pressure loss has been used widely [5, 9, 10, 15, 16, 19, 34, 35] to analyze the performance of nasal cavities. Especially, results of the ratio of the loss to the mass flux, or in other words, the Reynolds number, are helpful [5, 35] and can be compared to real rhinomanometry measurements [36] Streamlines are not only a great tool to analyze the pressure loss, but can also be used to understand the distribution of the flow in the nasal cavity. That is, if they are colored, e.g., by the velocity magnitude of the flow, one can identify accelerating and decelerating flow [10, 11, 13, 15, 21] and

hence positions of airway restrictions, i.e., locations that are potential regions for a surgery. Furthermore, streamlines deliver the possibility to analyze the mass flux distribution in the nasal cavity as they basically represent the fate of massless point-particles travelling through the nasal cavity. As such, they can be used to understand why patients have a diminished olfactory functionality, e.g., in cases where streamlines do not pass the olfactory organ at inspiration. Furthermore, they enable to identify where the flow penetrates the tissue, or in other words, where the flow impinges in the nasal cavity. Figure 9.3a shows an example of a streamline visualization. The flow distributes in all three turbinate regions and accelerates along the nasal cavity due to converging channels Penetration, however, can much better be analyzed by considering the wall-shear stress, which is the force acting on the tissue due to the passing flow. The wall-shear stress is computed by taking the derivative of the fluid velocity in

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flux-diminishing channels, which could be potential candidates for a surgery. The aforementioned evaluations did not consider the capability of the nasal cavity to temper the inhaled air. A healthy nasal cavity is, under the assumption of moderate ambient temperatures, capable of increasing the temperature lower turbinate up to almost body temperature before the fluid enters the lung. Hence, the temperature difference from the nostrils to the pharynx can be used to characterize the heating capability of a nasal cavity. Prescribing an ambient outside temperature at the nostrils and the body temperature at the tissue surface inside the nasal cavity allows to simulate the temleft nostril perature distribution. An example of the temperature pharynx right paranasal sinus ­distribution in a nasal cavity can be found in Fig. 9.4a. It has to be mentioned that the inhalation of cold air also decreases b tau the tissue temperature locally. To also model this effect, the heat transfer into the solid needs to be simulated as well. 0.8 This, however, leads to a multi-physics problem, the necessity to model tissue properties, and new algorithmic chal0.5 lenges, i.e., finding coupling and parallelization strategies 0.2 that efficiently solve such problems on HPC systems. Since the identifation of tissue properties is quite challenging and multi-physics implementations drastically increase code 0 complexity, the simulation of the heat transfer is in general omitted although this may lead to loss of physical correctness. However, despite the fact that a fixed body temperature is assumed at the whole tissue wall, an approximate evaluaFig. 9.3  Streamline and wall-shear stress visualizations taken from tion of the heating capability of a nasal cavity can be derived [15, 27]. (a) Streamlines in the nasal cavity colored by the non-­ from the analysis of the temperature difference from nostrils dimensional velocity magnitude. (b) Non-dimensional wall-shear stress to pharynx. Similar to the wall-shear stress computation, the mapped to the tissue wall heat flux into the fluid can be evaluated by the temperature gradient at the wall. If the flow passes close to the tissue, i.e., in the case of higher local Reynolds numbers, where the wall-normal direction and multiplying it with the dynamic boundary layer is thin, the temperature gradient is strong and viscosity of the fluid. As such, in high Reynolds-number more heat is transferred into the fluid. In contrast, slow movflows with smaller boundary layers the velocity gradient at ing fluid and larger boundary layers lead to decreased heat the wall is much steeper than in cases where a fluid passes a fluxes. In the limit, when the fluid is at rest, the problem wall slowly. The wall-shear stress can simply be mapped to reduces to a simple heat diffusion problem as the convective the surface of the nasal cavity. An example of such a map- part of the corresponding governing equation vanishes. ping is shown in Fig. 9.3b. An analysis of the wall-shear Investigations of the heat flux and the temperature increase stress distribution helps to identify regions that suffer from have been performed in [3, 14, 15]. The findings clearly impinging fluid and potentially from inflammations. In addi- show the capability of CFD simulations to analyze in detail tion to such a qualitative analysis, the wall-shear stress can where most of the heat is transported into the fluid. This is also be analyzed with respect to locally appearing maxima for example the case in the nasal valve or in the vicinity of and by its surface-area averaged values. Especially, latter the turbinates. Furthermore, in [15] a comparison of the therapproach allows to juxtapose wall-shear stress behaviors of mal parameters for different nasal cavities revealed that those different nasal cavities. Corresponding wall-shear stress cavities that underwent a turbinectomy and hence having a computations for various nasal cavities have been performed smaller surface area to exchange heat with the fluid, suffer in [4, 8, 12, 14, 15, 19, 35]. These investigations show that from a reduced heating capability. the wall-shear stress can be on the order of 1 Pa and that As mentioned above, the Reynolds number defines the locally even higher stresses may occur, which may lead to ratio of inertial forces to the viscous forces. It is a non-­ inflammations inferred by the irritation of endothelial and dimensional number that is commonly used in fluidmechanepithelial cells. Furthermore, the evaluation of the wall-shear ics to characterize the flow, i.e., if it is laminar, transitional, stress enables to identify local separation regions and small or turbulent. In nasal cavity flows the Reynolds number can, a

center turbinate

9  Application of Computational Fluid Dynamics Methods to Understand Nasal Cavity Flows

e.g., be defined by a reference velocity u that corresponds to a specific volume flux, the hydraulic diameter D = 4 · A/C with A being the area of the pharynx cross-section and C its circumference, and 𝑣 is the kinematic viscosity of air. As the velocity and the hydraulic diameter varies along the nasal cavity, it is obvious that the local Reynolds number Rel also varies. In healthy nasal cavities, Rel at peak inspiration at the pharynx is usually in the range of Rel ∈ (1000, 3000) and hence laminar to transitional, whereas in pathological cases the flow indeed may can become turbulent for locally larger Reynolds numbers [2, 5, 15, 16]. As such, strong fluctuating velocities emerge, which stem from small-scale vortical structures that are shed, e.g., from strong diameter variations or sharp corners. Such phenomena increase the energy loss and hence contribute to the overall pressure loss of a nasal cavity. There exist several methods to analyze secondary flow structures like high-energetic vortices. Often such vortices are visualized by using some strain-rate-based vortex detection criteria, e.g., the λ2-, Q-, or the ∆-criterion [37], to name just a few. Furthermore, the turbulent kinetic energy k that is derived from the Reynolds stresses can be used to identify high energetic regions in the flow field. An example of transitional flow in the pharynx region is depicted in Fig. 9.4b. For statistical analyses, the fluctuating flow is recorded over time at specified locations of interest. From the resulting time series, the frequency spectrum at such probe locations and correlations between different locations can be analyzed, i.e., information is gathered on the frequency of shed vortices and how information that is generated at one location is transported to another location. This helps to understand the fate of vortices, how they break up into smaller vortices, which way they are going, and if flow is turbulent or not. In [15, 16, 19], such in-depth analyses of the transitional or turbulent effects in respiration are investigated for the flow in the human nasal cavity, the larynx, and the trachea. In more detail, in [15, 19] energy spectra are used to show the mesh independence of the given solutions and to characterize the energy content of the flow at certain probe locations. Lintermann et al. [15] also present an analysis of eddy turnaround times by means of auto-correlations. They juxtapose cross-correlations to find correlating locations in the flow field and the turbulent kinetic energy is investigated similarly to [16]. CFD methods enable to investigate another essential functionality of the nasal cavity, namely its filtering function, i.e., the ability of catching particles that are dissolved in the fluid at inspiration. Examples of such particles are pollen, pollutants like fine dust particles or diesel aerosols, or even bacteria and other pathogens. For steady or time-averaged flow fields in which the according flow field does not change anymore, a particle simulation can be performed a posterior in a post-processing step of a flow computation. In contrast, highly unsteady flow fields require to track particles at CFD simulation run time. Frequently used approaches involve solving particle dynamics in addition to the governing

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e­quations of the flow. That is, in addition to an Eulerian ansatz for the flow, a Lagrangian ansatz for the particles is followed. In steady or averaged flow fields, the equation of motion for a particle uses the information of the non-changing flow field, which can be read from disk. In the unsteady case, an online-coupling for the solver of the fluid and the particle phase is necessary. It is obvious that the change of location of the particles also changes the workload per computational core, as they travel from one computational core to another. This leads to new parallelization issues that complicate implementations for efficient computation. Possible solutions either separate the solvers for flow and particle computation physically, which requires to communicate velocities across the according cores, or couple them directly on the core, where imbalance problems might appear [18]. Note that such implementations mainly realize only a onesided coupling, i.e., it is assumed that the particles are small, are transported by the motion of the fluid, and do not influence the flow. An analysis of the deposition behavior using particle simulation methods enables to evaluate the filtering function of the nasal cavity. Furthermore, this also allows for efficiency estimations of drug delivery under certain flow conditions, e.g., for respiration at rest or by considering sniffing processes. Several publications investigate particleladen flow in the nasal cavity [6, 8, 17, 18, 20]. Shang et al. [17] analyze the influence of including facial features into the simulation and indeed find a difference in the deposition behavior to not including them. In contrast, in [6, 8, 18, 20], only the nasal cavity from the nostrils to the pharynx is considered and analyses are performed for different Reynolds numbers and particle sizes and particle/air density ratios. Particularly in [20], the focus is on drug delivery, i.e., on biopharamceuticals that are targeted at the olfactory cleft to treat brain pathologies. Basically, all investigations show that the nasal valve filters a certain amount of the particles and that small channels also increase the deposition behavior. However, this is strongly dependent on the Reynolds number, which varies for respiration at rest, under workout, or performing a sniff, the individual geometry, and the particle size and density ratio. It should be noted that in none of the aforementioned publications a tissue movement or the inclusion of nasal hair is included.

9.5

 otentials of Using CFD Methods in P Clinical Applications

The methods described in Sect. 9.4 allow for patient-specific diagnoses and treatments, e.g., by supporting planning of surgical interventions or drug delivery disperses. Full DNS computations require to run simulations at present for several hours on tens of thousands of cores to solve a problem on meshes with a number of cells on the order of O(109). Hence, an integration of such methods into clinical

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applications is currently not feasible and only make sense for identify irritated regions that are potential candidates for research institutions that are interested in all detail of the a surgery. The heating capability and the heat flux distriflow physics. However, computing power becomes more and bution help to identify the origin of lung diseases, i.e., if a more inexpensive, which makes the use of LES more and nasal cavity is able to heat up the air to body temperature. more attractive. It should be noted that the continuous Statistical analyses and the visualization of vortex criteria increase of computational power will also make the integrafurthermore add to the understanding if a flow is laminar, tion of DNS into clinical applications possible in the near transitional, or turbulent. These methods enable to localfuture. It is expected that with the introduction of exascale ize high energetic regions that produce secondary flow HPC systems such simulations may be performed patient-­ structures increasing the pressure loss. specifically on demand. The integration of RANS computa- Planning a surgery hence would greatly benefit from such tions is already possible nowadays but, as elaborated in Sect. a detailed analysis that considers the geometry and the 9.3, RANS should not be the method of choice due to its pathology of the individual patient. Creating diagnostic disadvantages for accurately predicting low-Reynolds numtools based on CFD computations requires, however, ber flows in complex geometries. Potentials that arise from interdisciplinary cooperations between fluid-mechanics the integration of CFD into the clinical work routine are specialists, HPC and medical experts such that surgeons can optimally be supported. • Pre-surgical analyses of a nasal cavities from a fluid-­ • Analysis of the effectiveness of standardized surgery mechanics point of view techniques It is obvious that the methods described in Sect. 9.4 add to • The outcome of surgeries is often not known and surgeons the understanding of the intricate flow in the human nasal rely on their experience when it comes, e.g., to the ablacavity. They help to analyze why patients have problems tion or removal of tissue in the nasal cavity. CFD methin breathing by considering either the pressure loss along ods, however, may help to better understand the outcome a streamline or the total area-averaged pressure loss along of standardized surgery methods by performing pre- and the whole nasal cavity. Streamlines allow for an analysis post-surgical simulations. Hospital databases contain a of the mass flux distribution, where most of the fluid is large amount of medical image data sets, which hold passing the nasal cavity, and if the air is guided past the information on the pathological state before a surgery and olfactory organ. Wall-shear stress computations allow for the post-surgical state. Using those images as a basis for an evaluation of the forces acting on the tissue and help to an analysis of the change in pressure loss, the wall-shear a

b

center turbinate

left cavity

vorticity right cavity

lower turbinate

right nostril pharynx

votex stretching

voticity production zone

left paranasal sinus small scale vortices

pharynx

Fig. 9.4  Temperature distribution and visualization of transitional flow in the pharynx. Images were taken from [15, 27]. (a) Non-dimensional temperature distribution in the human nasal cavity. (b) Instantaneous

transitional flow in the pharynx in a pathological nasal cavity. Vortices are detected by the ∆-criterion and the contours are colored by the vorticity

9  Application of Computational Fluid Dynamics Methods to Understand Nasal Cavity Flows

• •

• •

•

stress distribution, and heating capability, it is possible to evaluate the method of surgery and to identify and predict successful procedures. Additionally, by using pre-surgical image data and the corresponding extracted surfaces in virtual operations, doctors can be trained to perform better surgeries as they get direct feedback from the results of CFD simulations. Future robotic systems could furthermore be tuned with respect to the CFD results to enhance surgery outcomes. Shape-optimization of nasal cavities Combining flow computations with shape optimization techniques is a natural extension of the existing methods. This way, surgeons will be able to define regions of the nasal cavity that they would consider for an operation. The three-dimensional surface representation extracted from medical images serves as a model that a virtual surgery could be performed on. The outcome of such a virtual surgery is a labeling that defines tissue segments to be removed and for which an optimal shape is a priori not known. Using then, in conjunction with CFD methods, shape optimization algorithms, e.g., adjoint-based methods, steepest-gradients, or implementations of sensitivity functions, it is possible to find optimal shapes that minimize or maximize certain objective functions. As such, the pressure loss or the wall-shear stress can be subject to minimization, while the heat flux or the heating capability should be maximized. The output is a surface that fulfills these constraints and which can be used as a template for a surgery. Note that such approaches have not been performed so far and that shape optimization for CFD is an expensive method and is still an active field of research. Drug-delivery optimization Using coupled flow and particle simulations, it is possible to track individual particles in an unsteady flow. This enables to optimize the delivery of drugs via the olfactory cleft to the human brain or to treat allergic rhinitis. Sprays are commonly used for such treatments, i.e., small vials with spray nozzles that break up the fluid into small ligaments and finally into separate droplets upon pumping. Obviously, the nozzle position and the type of respiration determine the fate of the drug. By numerical simulation, the optimal location, nozzle insertion angle, and respiration type for the individual application and even patient can be determined to maximize the effectiveness of the drug. Enhancement of rhinological diagnoses with the help of machine learning techniques The collection of all available patient data, i.e., image data, diagnostic data such as anamese reports, rhinomanometer measurements, and historical reports in combination with simulation results enable the use of machine learning measurements, and historical reports

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in combination with simulation results enable the use of machine learning techniques to support surgical diagnoses. That is, segmentation of CT data could be performed fully automatically with the help of articifical neural networks, pathologies could be classified automatically, flow physics could be predicted by means of physicsbased learning methods circumventing expensive CFD computations, and pathological features could be extracted automatically and presented to the medical doctor for further consideration.

References 1. Naftali S, Schroter RC, Shiner RJ, Elad D. Transport phenomena in the human nasal cavity: a computational model. Ann Biomed Eng. 1998;26(5):831–9. 2. Hörschler I, Meinke M, Schröder W. Numerical simulation of the flow field in a model of the nasal cavity. Comput Fluids. 2003; 32(1):39–45. https://doi.org/10.1016/S0045-7930(01)00097-4. 3. Naftali S, Rosenfeld M, Wolf M, Elad D. The air-conditioning capacity of the human nose. Ann Biomed Eng. 2005;33(4):545–53. https://doi.org/10.1007/s10439-005-2513-4. 4. Elad D, Naftali S, Rosenfeld M, Wolf M. Physical stresses at the air-wall interface of the human nasal cavity during breathing. J Appl Physiol. 2006;100(3):1003–10. https://doi.org/10.1152/ japplphysiol.01049.2005. 5. Hörschler I, Schröder W, Meinke M. On the assumption of steadiness of nasal cavity flow. J Biomech. 2010;43(6):1081–5. https:// doi.org/10.1016/j.jbiomech.2009.12.008. 6. Shi H, Kleinstreuer C, Zhang Z. Dilute suspension flow with nanoparticle deposition in a representative nasal airway model. Phys Fluids. 2008;20(1):013301. https://doi.org/10.1063/1.2833468. 7. Zachow S, Muigg P, Hildebrandt T, Doleisch H, Hege HC. Visual exploration of nasal airflow. IEEE Trans Vis Comput Graph. 2009;15(6):1407–14. https://doi.org/10.1109/TVCG.2009.198. 8. Gambaruto A, Taylor D, Doorly D. Modelling nasal airflow using a Fourier descriptor representation of geometry. Int J Numer Methods Fluids. 2009;59(11):1259–83. https://doi.org/10.1002/fld.1866. 9. Riazuddin VN, Zubair M, Shuaib IL, Abdullah MZ, Hamid SA, Ahmad KA. Numerical study of inspiratory and expiratory flow in a human nasal cavity. J Med Biol Eng. 2010;31(3):201–6. https:// doi.org/10.5405/jmbe.781. 10. Lintermann A, Meinke M, Schröder W. Investigations of nasal cavity flows based on a lattice- Boltzmann method, in: Resch M, Wang X, Bez W, Focht E, Kobayashi H, Roller S (Eds.), High performance computing on vector systems 2011, Springer Berlin, 2012, pp. 143–158. doi:https://doi.org/10.1007/978-3-642-22244-3. 11. Lintermann A, Meinke M, Schröder W. Investigations of the Inspiration and Heating Capability of the Human Nasal Cavity Based on a Lattice-Boltzmann Method. In: Proceedings of the ECCOMAS Thematic International Conference on Simulation and Modeling of Biological Flows (SIMBIO 2011), Brussels, Belgium, 2011. 12. Gambaruto AM, Taylor DJ, Doorly DJ. Decomposition and description of the nasal cavity form. Ann Biomed Eng. 2012;40(5):1142– 59. https://doi.org/10.1007/s10439-011-0485-0. 13. Achilles N, Pasch N, Lintermann A, Schröder W, Mösges R. Computational fluid dynamics: a suitable assessment tool for demonstrating the antiobstructive effect of drugs in the therapy of allergic rhinitis. ActaotorhinolaryngologicaItalica: organoufficialedella

84 Societ’aitaliana di otorinolaringologia e chirurgiacervico-­facciale. 2013;33(1):36–42. 14. Kim SK, Na Y, Kim JI, Chung SK. Patient specific CFD models of nasal airflow: overview of methods and challenges. J Biomech. 2013;46(2):299–306. https://doi.org/10.1016/j. jbiomech.2012.11.022. 15. Lintermann A, Meinke M, Schröder W. Fluid mechanics based classification of the respiratory efficiency of several nasal cavities. Comput Biol Med. 2013;43(11):1833–52. https://doi.org/10.1016/j. compbiomed.2013.09.003. 16. Bates AJ, Doorly DJ, Cetto R, Calmet H, Gambaruto AM, Tolley NS, et al. Dynamics of airflow in a short inhalation. J R Soc Interface. 2014;12(102):20140880. https://doi.org/10.1098/ rsif.2014.0880. 17. Shang Y, Inthavong K, Tu J. Detailed micro-particle deposition patterns in the human nasal cavity influenced by the breathing zone. Comput Fluids. 2015;114:141–50. https://doi.org/10.1016/j. compfluid.2015.02.020. 18. Henn T, Thäter G, Dörfler W, Nirschl H, Krause MJ. Parallel dilute particulate flow simulations in the human nasal cavity. Comput Fluids. 2016;124:197–207. https://doi.org/10.1016/j. compfluid.2015.08.002. 19. Calmet H, Gambaruto A, AM BAJ, Vázquez M, Houzeaux G, Doorly DJ. Large-scale CFD simulations of the transitional and turbulent regime for the large human airways during rapid inhalation. Comput Biol Med. 2016;69:166–80. https://doi.org/10.1016/j. compbiomed.2015.12.003. 20. Engelhardt L, Röhm M, Mavoungou C, Schindowski K, Schafmeister A, Simon U. First steps to develop and validate a CFPD model in order to support the Design of Nose-to-Brain Delivered Biopharmaceuticals. Pharm Res. 33:1337. https://doi. org/10.1007/s11095-016-1875-7. 21. Eitel G, Freitas RK, Lintermann A, Meinke M, Schröder W. Numerical simulation of nasal cavity flow based on a lattice-­ Boltzmann method. In: Dillmann A, Heller G, Klaas M, Kreplin HP, Nitsche W, Schröder W, editors. New results in numerical and experimental fluid mechanics VII, 112 of notes on numerical fluid mechanics and multidisciplinary design. Berlin: Springer; 2010. p. 513–20. 22. Lorensen WE, Cline HE. Marching cubes: a high resolution 3D surface construction algorithm. ACM SIGGRAPH Computer Graphics. 1987;21(4):163–9. 23. Taubin G, Zhang T, Golub G. Optimal surface smoothing as filter design. Computer Vision ECCV. 1996;96:283–92.

A. Lintermann 24. Fedorov A, Beichel R, Kalpathy-Cramer J, Finet F-RJJC, Pujol S, et al. 3D slicer as an image computing platform for the ­quantitative imaging network. Magn Reson Imaging. 2012;30(9):1323–41. https://doi.org/10.1016/j.mri.2012.05.001. 25. Nolden M, Zelzer S, Seitel A, Wald D, Müller M, Franz AM, et al. The medical imaging interaction toolkit: challenges and advances. Int J Comput Assist Radiol Surg. 2013;8(4):607–20. https://doi. org/10.1007/s11548-013-0840-8. 26. Rosset A, Spadola L, Ratib O. Osiri X. an open-source software for navigating in multidimensional DICOM images. J Digit Imaging. 2004;17(3):205–16. https://doi.org/10.1007/s10278-004-1014-6. 27. Lintermann A, Schlimpert S, Grimmen J, Günther C, Meinke M, Schröder W. Massively parallel grid generation on HPC systems. Comput Methods Appl Mech Eng. 2014;277:131–53. https://doi. org/10.1016/j.cma.2014.04.009. 28. Chien KY. Predictions of channel and boundary-layer flows with a low-Reynolds-number turbulence model. AIAA J. 1982;20(1):33– 8. https://doi.org/10.2514/3.51043. 29. Wilcox DC. Formulation of the k-omega turbulence model revisited, in: 45th AIAA aerospace sciences meeting and exhibit, American Institute of Aeronautics and Astronautics, Reston, Virigina, 2007. doi:10.2514/6.2007-1408. 30. Anderson JDJ. Computational fluid dynamics. Singapore: MacGraw-Hill; 1995. 31. Succi S. The lattice Boltzmann equation: theory and applications, vol. 222. Rome: Oxford University Press; 2001. 32. Kopriva DA. Implementing spectral methods for partial differential equations, scientific computation. Dordrecht: Springer. https://doi. org/10.1007/978-90-481-2261-5. 33. Bernoulli D. Hydrodynamica, sive de viribus et motibusfluidorumcommentarii: opus academicumabauctore, dumPetropoliageret, congestum, 1738. doi:https://doi.org/10.3931/e-rara-3911. 34. Finck M, Hänel D, Wlokas I. Simulation of nasal flow by lattice Boltzmann methods. Comput Biol Med. 2007;37(6):739–49. https://doi.org/10.1016/j.compbiomed.2006.06.013. 35. Hörschler I, Schröder W, Meinke M. Comparison of steady and unsteady nasal cavity flow solutions for the complete respiration cycle. Comput Fluid Dyn J. 2006;15(3):354–77. 36. Vogt K, Hoffrichter H. Neueströmungs physikalische Erkenntnisse in der Rhinomanometrie und ihrepraktischenKonsequenzen. In: Mösges S, editor. TopischeTherapie der allergischen Rhinitis. Germany: Biermann; 1993. p. 45–60. 37. Haller G. An objective definition of a vortex. J Fluid Mech. 2005;525:1–26. https://doi.org/10.1017/S0022112004002526.

The Evaluation of the Nose, Nasal Cavity and Airway

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Kazım Bozdemir, Hakan Korkmaz, and Christine B. Franzese

10.1 Introduction Congestion of the nasal passages, which frequently arises from the interaction of several different processes concerned with blood flow and inflammation, can occasion obstruction of the airways ranging from moderate to severe. There is an abundant blood supply to the epithelium of the nose, and its volume may grow or shrink swiftly under the influence of heat, chemical stimulation, mechanical factors or neural inputs [1]. The nasal cycle consists in the physiological switching of congested and decongested states, reflecting shifts in nasal blood volume, in normal individuals [2]. Inflammatory processes, by contrast, involve increased numbers of cells and the leakage of plasma into the extravascular compartment and thus may worsen any nasal blockage resulting from vasodilation [1]. Assessment of nasal patency when the nose is congested is typically only needed in a clinical setting where either surgery is being contemplated or the patient’s main issue is a result of moderate or severe nasal obstruction [3]. In an ideal world, any test for the patency of the nose would have the following characteristics: straightforward, readily interpretable, valid for a reasonable period and with excellent cost-­ effectiveness, possessing a standard implementation, non-invasive, swift and reproducible, giving detailed information and capable of being used with all patients. In the real world, the tests allowing objective appraisal at the clinician’s disposal are rhinomanometry, peak nasal inspiratory flow (PNIF), and acoustic rhinometry (AR). Lately, four-phase rhinomanometry (4PR) has joined the other older techniques in clinical application [4].

K. Bozdemir (*) · H. Korkmaz Department of Otorhinolaryngology, Medical Faculty, Yıldırım Beyazıt University, Ankara, Turkey C. B. Franzese Department of Otolaryngology-Head and Neck Surgery, University of Missouri, Columbia, MO, USA e-mail: [email protected]

There is a need for objectivity in the testing of nasal patency arising from medicolegal, diagnostic and documentary purposes. At the current time, three such objective techniques exist: active anterior rhinomanometry (AAR), 4PR and AR. There have been a number of overviews of the field, setting down the area of interest and the technological limitations. Such an overview comes from clinical guidelines, expert consensus statements and the International Committee on Standardisation [5]. AR is a technique dependent upon acoustic reflectance to calculate cross-sectional areas of the nasal cavity at various points [6, 7]. NPIF provides measurement of the passage of air through the nasal cavity during inspiration [7]. Between them, they possess the ability to diagnose nasal obstruction in some 80–95% of cases. The techniques have been validated on different occasions against each other for both confirmation of the abnormal anatomy and to give diagnostically useful measures of nasal inspiratory function [8–16].

10.2 Rhinomanometry At present, rhinomanometry is the sole technique in use, which can give a quantitative measure to the respiratory function of the nose [17]. Both the pressure and the flow rate of the air inspired are subject to measurement, and nasal resistance can be duly calculated from them. The usual procedure is to obtain measurements during four breathing cycles through the nose, with resistance calculated for an inspiratory pressure difference of 75 Pa. Figure 10.1 [18] illustrates a pressure flow curve (i.e. rhinomanometry graph). The maximum resistance in normal individuals is 0.3 Pa mL−1 s−1 [18]. Rhinomanometry provides the best measurement of the function of the nose and what response occurs as a result of the use of a decongestant spray, a vital fact in the assessment of cases where hypertrophy of the inferior turbinate is thought to be responsible for nasal obstruction. Hypertrophied inferior turbinates are amongst the most frequently ­encountered reasons for nasal obstruction. It has been dem-

© Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_10

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Fig. 10.1  Pressure flow curve generated with a posterior rhinomanometry test

onstrated by Berger et  al. [2] that the hypertrophy is the result of a thickened lamina propria or submucosa, in comparison with non-diseased turbinates. The submucosal layers are those which respond to decongestants. The majority of those writing in this field would accept as indicative of good response a reduction in the airway resistance of 30%, as confirmed by rhinomanometry, and as pointing to the likelihood that the patient would benefit from submucosal reduction by powered surgical instrumentation [19–21]. Rhinomanometry is used standardly in diagnosis to assess how effectively the nose is functioning during breathing. It works by computing the pressure and flow rates obtained in the normal respiratory cycle. Raised pressures whilst breathing are a consequence of more resistance to the flow of air through the nose (i.e. obstruction). Similarly, if flow has increased, that means the airway within the nose is more patent. Nasal resistance, in other words, is a measure of the degree of obstruction present. Where the nostrils are assessed separately, this is termed anterior rhinomanometry (AntR). Where both nostrils are assessed at the same time, this is posterior rhinomanometry (PostR) [22]. The procedure for AntR involves the subject assuming an upright sitting position, then clearing the nose prior to the introduction of a sensing tube unilaterally, leaving the contralateral nostril as it is. A mask covers the face snugly and is joined to the sensing tube. Measuring one side at a time permits the assessment of any asymmetry or defect within the airways of the nose. By measuring prior to and following administration of a nasal decongestant intranasally, the contribution of congestion to the overall resistance can be calculated. Where administering a decongestant fails to increase

K. Bozdemir et al.

patency, the likely problem is anatomical, for example cartilaginous or bony deformities. The technique may reveal that such an abnormality exists and lateralise the lesion, but cannot more precisely pinpoint its location. To do that, we need either endoscopy or acoustic rhinometry. Anterior rhinomanometry is frequently employed, not least thanks to its easy implementation. However, it is worth remarking that reproducibility of the technique depends on keeping the room temperature and level of humidity constant, ensuring the face mask has a snug fit and closing off the unmeasured nostril whilst stopping the subject using his/her mouth to breathe. The patient’s subjective sense of the nose being blocked does not invariably correspond to an abnormal measurement in this objective technique. For PostR, a more skilled operator is needed and the patient must be capable of following instructions to the letter [22]. AntR assesses the flow of air on one side of the nose [23]. The assessment is of both sides, one after the other [24]. AntR and acoustic rhinometry are likely to be the most widespread ways to measure the flow of air for clinical purposes [25]. AntR gives a reading for transnasal pressure, the variation in pressure between the nostrils and the nasopharynx. In this technique, a probe to record pressure is sited at the external opening of the nostril not under test [25]. The nasal airway is in effect a long tube, the pressure of which as recorded at the nostril of the side not under test is assumed to equal that of the nasopharynx. How much the nose resists the passage of air can then be computed using two measurements, one on each side. If the septum is not intact, however, AntR cannot measure total resistance [23]. Postnasal rhinomanometry, on the other hand, utilises a probe to detect the pressure in the nasopharynx. It is introduced by way of the nasal floor into the nasopharynx [23]. A different sensor records the pressures at the entrance of the nose [25]. Thus the transnasal pressure differential is calculated [23]. PostR (posterior rhinomanometry) necessitates positioning a pressure detector in the posterior throat, gaining access via the mouth. The pressure variation between nostrils and nasopharynx can be read. This technique allows the complete resistance to be assessed in a direct way. Subjects need training to preserve the mouth tube in situ [24]. Rhinomanometric techniques may assist with sorting out whether an anatomical defect or mucosal factors are blocking nasal airflow. For this purpose, a decongestant agent is employed. Likewise, how effective some interventions, such as nasal steroid sprays, are, can be measured in a quantitative manner. Rhinomanometry is used to assess the patency of the nose when an allergen is used for nasal challenge, comparing before and after measurements. Where resistance to airflow has been quantitatively demonstrated following allergenic challenge, there is objective confirmation of allergy to an airborne antigen, even where other tests appear negative [22].

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10.3 Four-Phase Rhinomanometry (4PR) Vogt pioneered high-resolution rhinomanometry in 1986 [26]. During recording, on the X–Y mirror display, there appears to be a shift in phase whilst breathing in and out and this causes an apparent hysteresis. It was long considered that the hysteresis was produced by the equipment used for measuring rather than representing some inherent property of breathing and that it could be eliminated mathematically, giving a graph showing a single line of regression rather than a loop shape. But Vogt and colleagues [27] considered that the hysteresis did represent some property of the airstream. Thus, the true graph of pressure and flow would have a looped appearance rather than the sigmoidal shape that passes through the origin that mathematical correction produces (see Fig. 10.2). Therefore, the phase shift (hysteresis) affecting the relationship of pressure differential and airflow has been explained as due to: • The inertia within the airstream. • The fact that the anatomical structures involved possess a degree of elasticity [3, 26, 27]. Thus, 4PR is not used to calculate a numerical function found by regression, but it directly measures the way the airflow within the nose changes under physiological conditions. Vogt et al. [2, 27] in fact brought in new parameters, such as vertex resistance (i.e. how much resistance is encountered at

peak flow). This parameter is problematic, though, due to there being no simple relationship between vertex resistance and the combined resistance to flow of air presented by the nose [3]. Yet another parameter introduced was “effective resistance” (calculated by taking 2000 recordings of flow and pressure difference and summing them then dividing by the total number). One drawback with this parameter is that it leads to loss of understanding of how the flow and pressure are related, and unless reference pressures are fully known, it is challenging to compare resistance values between different subjects. The loop diagram produced by 4PR appears to be a consequence of how the nasal valve functions and how much the mask is deformed by extreme pressures, say 600– 1000  Pa. The loop is more open, some authorities assert, whilst breathing in. Such an air pressure will make the nostrils collapse in normal individuals [3]. Bridger [28] proved that the nasal valve of individuals lacking nasal disease collapses when 600  Pa pressure has been reached. For diseased individuals, collapse occurs before then. So in evaluating nostril collapse, the key figure is the pressure whilst breathing in that produces such an effect. The upper and lower parts of the loop have only limited clinical significance. Vogt and colleagues [2] presented a case of collapsing nostrils where surgery reduced the effect; however, the pressures involved following surgery were a long way (300–600 Pa) from those studied pre-operatively. Gross and colleagues [29] asserted that the phase shift is not a property of how nasal airflow occurs but rather produced by the way measurements are taken. They contend that the hysteresis is not reflective of airflow characteristics such as inertia, variable resistance or the organization of flow, but is a product of a ‘storage effect’ resulting from compressibility (the derivate of density). If the rate of airflow is recorded away from the nose, the storage effect causes the relationship between flow rate and pressure to be disturbed, which appears as a hysteresis. The hysteresis seen in rhinomanometry can be satisfactorily explained solely on the basis of mass conservation.

10.4 Acoustic Rhinometry (AR)

Fig. 10.2  General shape of rhinomanometric graphs in four-phase rhinomanometry

Acoustic rhinometry is also used standardly to provide quantitative measurement of how patent the nose is. The data come from the patterns produced by sending sound waves into the nasal cavity. These data then provide information on the geometry of the inside of the nose. Using acoustic ­rhinometry, areas of narrowing that can cause nasal obstruction can be pinpointed. Unlike rhinomanometric techniques, it cannot comment on how the nose actually functions nor quantify parameters of respiration. An acoustic rhinometer produces a sound wave propagated via tubing into a nostril

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on one side. The magnitude and pattern of the echo can generate information about the shape and size of the nasal interior, the time to reflection being a function of the distance to the obstacle of which it reflects. Interpreting the pattern of the echo into an actual nasal volume is done by the attached computer, which relies on theoretical assumptions and formulas to calculate the parameters. If a nose is blocked, whether by polyps or neoplasm or some other cause, the narrowest portion of the airway will be deep inside. At what depth the lesion occurs can be predicted by acoustic rhinometry, but not the nature of the lesion [30]. Acoustic rhinometry also has a role in evaluating the effectiveness of long-term pharmacological interventions to address nasal obstruction in rhinitis, rhinosinusitis or polypoidosis. Since the technique can be used to calculate the volume of the nasal cavity, it can quantify the extent that polyps have diminished following medical therapy. For nasal challenges wherein allergens are applied directly to the lining of the nose, the technique allows quantification of the volume loss brought about by congestion. It is, nonetheless, worthy of note that the quantitative determinations of neither acoustic rhinometry nor rhinomanometry have a close relationship with how blocked patients report their noses to feel [30]. Acoustic rhinometry is amongst the most recent additions to the arsenal of techniques for quantifying aspects of the interior of the nose from the nares to the choanae in a swift, non-invasive way that puts minimal onus on the patient to co-operate with the investigation [31–33]. Acoustic rhinometry depends on computing nasal parameters on the basis of data collected about the reflection of sound waves sent into the cavity that may be attenuated and relatively delayed by different nasal barriers [6]. In this way, cross-sectional areas can be computed through the nasal cavity, particularly in the area of the nasal valve and the anterior and posterior turbinates, plus the determination of the volume of the nasal interior. The specific points at which constriction occurs can be highlighted, since these influence the resistance to airflow [34, 35] and the geometry of the airways within the nose proper and the nasopharynx may be deduced [36]. Clinically speaking, acoustic rhinometry provides value to the clinician through the capability of knowing the topometry of the internal nose, a key asset in following up cases seen in rhinology clinics [6, 37]. Whilst the nature of blockage is not shown, the degree of severity of obstruction is revealed in an objective manner at specific intervals and it thus has particular pertinence to the assessment of nasal patency [38–40], alongside other aspects of clinical assessment. Schroeder was the first [41] to use sound waves and their reflections to quantify parameters of the airway in man, whilst investigating the topological basis of the vocal tract. Hilberg and colleagues then led the way in applying the method to understand nasal topology [6]. These authors then

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showed the correlation between measurements obtained acoustically with those obtained by CT, MRI and saline volume techniques in several publications, alongside claims for the ability to assess nasal topology. Using acoustic rhinometry, it is possible to ascertain the cross-sectional area of the nasal cavity at any point within the nose. A two-dimensional picture thus emerges. It works by comparing the amplitude of reflected waves against the incident wave (proportionate to cross-sectional area) and time to return to source (which translates into distance travelled). Early versions used a click generator, but it was subsequently demonstrated by Djupesland et al. [42] that both clicks and wide band signals produced comparable curves. In a nose that remains congested, there are three points at which the area tends to the minimum, appearing as notches on the curve. Typically, a particular narrowing is found 3 cm beyond the entrance to the nostril. Indeed, two such narrowings have been reported on in this region [42]. Figure 10.3 shows what the acoustic rhinometry trace looks like [43]. Fisher [44] laid particular emphasis on where the method’s use is limited: 1. A narrowing in the nasal cavity that leads to a cross section less than 0.6–0.7  cm2 leads to underestimating the area deeper within the nose and hence the nasal volume. 2. As distance from the nostrils increases, the method becomes progressively less accurate. Lenders and colleagues [45] have defined an ‘I-notch’ (the isthmus nasi) and a ‘C-notch’ (corresponding to the head of the inferior turbinate), which can be observed on the area-distance plot. Following a procedure designed to pro-

Fig. 10.3  Acoustic rhinometry trace. MCA minimal cross-sectional area, Inf. turb. inferior turbinate

10  The Evaluation of the Nose, Nasal Cavity and Airway

duce nasal decongestion, the ‘descending W’ that was present initially on the trace morphed into an ‘ascending W’ as the area at the turbinate head enlarged.

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In measuring NPIF, the mask must fit exactly correctly, being of sufficient size to eliminate pressing on the nostrils but not so large that the airtightness of the seal cannot be guaranteed [19]. Wihl and Malm [53] pointed out that a leaking face mask whilst performing NPIF/NPEF led to overesti10.5 Peak Nasal Inspiratory Flow (PNIF) or mation of the values. Underestimated values were due to the subject not allowing their soft palate to relax when breathing Nasal Peak Inspiratory Flow (NPIF) out with maximum force. The researchers observed that, A number of methods have been pioneered to allow quantifi- where the nose was partly blocked, there may be an increase cation of the degree of patency of the nose [46, 47]. Some of in pressure within the Eustachian tubes, resulting in an such techniques are nasal peak inspiratory or expiratory flow unwillingness to breathe out as hard as possible [53]. (NPIF and NPEF), anterior and posterior rhinomanometry, An inbuilt restriction on the use of nasal peak flow is that acoustic rhinometry and peak flow nasal patency index [48]. it cannot account for lung function that is pathological [53]. Spirometers may be adapted with a nasal piece to specifically Nasal peak flow is a function of both how patent the nasal measure FEV1, 1 s duration forced inspiratory volumes and airway is and how effectively the lungs work [53]. If there is FVC, all considered nasally rather than through the mouth a restriction on airflow lower down the respiratory tract, or as usual in spirometry [49, 50]. Peak flow and rhinomanom- if the mechanism of breathing itself is weak, this will influetry produce values that indicate physiological function. ence the values obtained. Phagoo and colleagues [55] have Rhinomanometry is described in an earlier section of this shown that NPIF and (somewhat less markedly) NPEF are chapter. Nasal peak flow indirectly measures nasal blockage affected by alterations in the airway diameter within the since constriction places limits on both peak inspiratory and lungs. NPIF and NPEF can wrongly support the notion that expiratory flow through the nose. The expense involved in the nose is patent if the subject puts little effort into the test, acquiring the relevant equipment influences which method is the changing lung resistance to airflow is greater than usual chosen, as well as practical considerations when setting up or there is little dynamic resistance to airflow in the nose. clinical trials [46]. The researchers propose comparing oral and nasal values Measuring peak flow via the nose: Undoubtedly, nasal for peak flow and peak inspiratory flow to eliminate such peak flow has the advantage that it is straightforward to mea- sources of error [55]. sure. Modifying a mini-Wright peak flow meter by substitutJust as the PEF in asthmatic subjects varies during the ing a snug-fitting facial mask in place of a mouthpiece is course of the day, so nasal peak flow is minimal in the mornadequate for the measurement of NPEF.  The technique is ing and maximal in the evening. A normal range for NPIF swift, non-invasive, low cost and comparatively simple. The and NPEF has not been established and published so far, equipment is easily taken from place to place and can be hence nasal peak flow can only be used for intraindividual utilised repeatedly. In use, the subject should breathe in to comparisons, albeit it has been suggested that NPIF above the maximal extent, then, with lips firmly held shut, expire 2.5 L/s can be taken as non-pathological [56]. nasally as forcefully as they are able [51]. The measurement What role nasal peak flow estimation plays in clinical is read off in L min−1. One possible problem with this tech- practice remains the subject of debate [57, 58]. Despite this nique is that mucus may be introduced into the peak flow disagreement, nasal peak flow is the sole technique usable meter [52]. for the assessment of circadian variation in naturalistic setAs an alternative, NPIF may be assessed by means of the tings, the variation from day-to-day and any ways the enviYoulten peak nasal inspiratory flow meter, which is a mini-­ ronment affects the degree to which the nose remains patent. Wright flow meter in reverse, and connected by a mask as Since it is portable, nasal blockage brought on by occupaused in resuscitation. To perform the manoeuvre, instruct the tion can be assessed quantitatively. Nasal peak flow may be subject to fit the mask snugly over both nose and mouth, used to quantify nasal patency prior to and following either keep lips firmly shut and take a forceful sniff to inspire maxi- allergen or medication administration both acutely and on a mally. In doing so, there is a slight chance the vestibulum of more chronic basis. As an illustration of this, nasal peak each nostril may collapse, but this effect may be counter- flow can be used to gauge the late phase reactions to an acted by flaring the nostrils by means of their attached mus- allergen once the patients return home from the clinic. The cles [53]. A study of 327 subjects who all had allergic efficacy of corticosteroid therapy on polyps may be folconditions found that just 2% (i.e. six subjects) were unable lowed up in like manner, and where septoplasty and turbito produce an NPIF reading due to the nose becoming totally nectomy are ­contemplated, nasal peak flow is of value both blocked in this way [53]. Newly published research demon- pre- and post-­operatively. Where the function of the nose is strates that nasal patency alone does not predict NPIF, which an issue, the technique helps, and is of value in the medicoalso depends in part on how compliant the nasal wall is [54]. legal field [46].

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Nasal function and evaluation, nasal obstruction. 4. Vogt K, Jalowayski AA, Althaus W, Cao C, Han D, Hasse Head and Neck Surgery: Otolaryngology. 2nd ed. New York, NY: W, Hoffrichter H, Mösges R, Pallanch J, Shah-Hosseini K, Lippincott\Raven; 1998. Peksis K, Wernecke KD, Zhang L, Zaporoshenko P. 4-Phase-­ 25. Cummings C.  Otolaryngology: head and neck surgery. St. Louis: Rhinomanometry (4PR)--basics and practice 2010. Rhinol Suppl. Mosby; 1999. 2010;21:1–50. 26. Vogt K.  Einfu¨hrung in die Rhinomanometrie. Berlin: Humboldt 5. Clement PA, Halewyck S, Gordts F, Michel O.  Critical evaluaUniversity; 1986. tion of different objective techniques of nasal airway assessment: 27. Vogt K.  High resolution rhinomanometry. In: Jahnke K (ed) 4th a clinical review. Eur Arch Otorhinolaryngol. 2014;271(10):2617– Eufos congress Berlin. Monduzzi editore, 2000, pp 113–114. 25. https://doi.org/10.1007/s00405-013-2870-9. Epub 2014 28. Bridger G, Proctor D. Maximum nasal inspiratory flow and nasal Jan 20 resistance. Ann Otol Rhinol Laryngol. 1970;79(3):481–8. 6. Hilberg O, Jackson A, Swift D, Pedersen O. Acoustic rhinometry: 29. Groß TF, Peters F. A fluid mechanical interpretation of hysteresis evaluation of nasal cavity geometry by acoustic reflection. J Appl in rhinomanometry. ISRN Otolaryngol. 2011;2011:126520. doi: Physiol. 1989;66(1):295–303. https://doi.org/10.5402/2011/126520. Print 2011. 7. Lam DJ, James KT, Weaver EM. Comparison of anatomic, physi 30. Acoustic rhinometry. EAACI. European Academy of Allergy and ological, and subjective measures of the nasal airway. Am J Rhinol. Clinical Immunology. http://www.eaaci.org/patients/diagnosis2006;20(5):463–70. and-treatment/allergy-specific-tests/acoustic-rhinometry.html. . 8. Hilberg O, Jensen FT, Pedersen OF. Nasal airway geometry: comAccessed 25 Aug 2015. parison between acoustic reflections and magnetic resonance scan 31. Melo AC, Gomes Ade O, Cavalcanti AS, Silva HJ.  Acoustic rhining. J Appl Physiol. 1993;75:2811–9. nometry in mouth breathing patients: a systematic review. Braz J 9. Corey JP, Gungor A, Nelson R, et  al. A comparison of the nasal Otorhinolaryngol. 2015;81(2):212–8. https://doi.org/10.1016/j. cross-sectional areas and volumes obtained with acoustic rhinomebjorl.2014.12.007. Epub 2014 Dec 29 try and magnetic resonance imaging. Otolaryngol Head Neck Surg. 32. Uzzaman A, Metcalfe DD, Komarow HD.  Acoustic rhinom 1997;117:349–54. etry in the practice of allergy. Ann Allergy Asthma Immunol. 10. Corey JP, Nalbone VP, Ng BA. Anatomic correlates of acoustic rhi2006;97(6):745–51. quiz 751-2, 799 nometry as measured by rigid nasal endoscopy. Otolaryngol Head 33. Djupesland P, Pedersen OF.  Acoustic rhinometry in infants and Neck Surg. 1999;121:572–6. children. Rhinol Suppl. 2000;16:52–8. 11. Holmstrom M, Scadding GK, Lund VJ, et al. Assessment of nasal 34. Hilberg O.  Objective measurement of nasal airway dimensions obstruction. A comparison between rhinomanometry and nasal using acoustic rhinometry: methodological and clinical aspects. inspiratory peak flow. Rhinology. 1990;28:191–6. Allergy. 2002;57(Suppl. 70):5–39. 12. Jones AS, Viani L, Phillips D, et  al. The objective assessment of 35. Trindade IEK, Gomes AOC, Sampaio-Teixeira ACM, Trindade nasal patency. Clin Otolaryngol. 1991;16:206–11. SHK. Adult nasal volumes assessed by acoustic rhinometry. Braz J 13. Wihl JA, Malm L. Rhinomanometry and nasal peak expiratory and Otorhinolaryngol (Engl Ed). 2007;73:32–9. inspiratory flow rate. Ann Allergy. 1998;61:50–5. 36. Kunkel M, Wahlmann U, Wagner W. Nasal airway in cleft-­palate 14. Min YG, Jan YJ. Measurements of cross-sectional area of the nasal patients: acoustic rhinometric data. J Cranio-Max Fac Surg. cavity by acoustic rhinometry and CT scanning. Laryngoscope. 1997;25:270–4. 1995;105:757–9. 37. Grymer LF.  Clinical applications of acoustic rhinometry. Rhinol 15. Mamikoglu B, Houser S, Akbar I, et al. Acoustic rhinometry and Suppl. 2000;16:35–43. computed tomography scans for the diagnosis of nasal septal 38. Roithmann R.  Testes específicos da permeabilidade nasal. Braz J deviation, with clinical correlation. Otolaryngol Head Neck Surg. Otorhinolaryngol. 2007;73:2. 2000;123:61–8. 39. Corey JP. Acoustic rhinometry: should we be using it? Curr Opin 1 6. Terheyden H, Maune S, Mertens J, et al. Acoustic rhinometry: valiOtolaryngol Head Neck Surg. 2006;14:29–34. dation by three-dimensionally reconstructed computer tomographic 40. Lal D, Corey JP.  Acoustic rhinometry and its uses in rhinology scans. J Appl Physiol. 2000;89:1013–21. and diagnosis of nasal obstruction. Facial Plast Surg Clin N Am. 17. Moore M, Eccles R.  Objective evidence for the efficacy of sur2004;12:397–405. gical management of the deviated septum as a treatment for 41. Schroeder M. Determination of the geometry of the human vocal chronic nasal obstruction: a systematic review. Clin Otolaryngol. tract by acoustic measurements. J Acoust Soc Am. 1967;41:1002. 2011;36:106–13. 42. Djupesland PG, Qian W, Furlott H, Rotnes JS, Cole P, Zamel 18. Murrell GL.  Components of the nasal examination. Aesthet Surg N. Acoustic rhinometry: a study of transient and continuous noise J. 2013;33(1):38–42. https://doi.org/10.1177/1090820X12469626. techniques with nasal models. Am J Rhinol. 1999;13(4):323–9. Epub 2012 Dec 7. 43. Krouse J, Lund V, Fokkens W, Meltzer EO. Diagnostic strategies in 19. Passali D, Passali FM, Damiani V. Treatment of inferior turbinate nasal congestion. Int J Gen Med. 2010;3:59–67. hypertrophy: a randomized clinical trial. Am Otol Rhinol Laryngol. 44. Fisher E.  Acoustic rhinometry. Clin Otolaryngol Allied Sci. 2003;112:683–8. 1997;22(4):307–17. 20. Liu C, Tan C, Lee F, et  al. Microdebrider-assisted versus 45. Lenders H, Pirsig W.  Acoustic rhinometry: a diagnostic tool for radiofrequency-assisted inferior turbinoplasty. Laryngoscope. patients with chronic rhonchopathies. Rhinol Suppl. 1992;14:101. 2009;119:414–8.

10  The Evaluation of the Nose, Nasal Cavity and Airway 46. Nathan RA, Eccles R, Howarth PH, Steinsvåg SK, Togias A. Objective monitoring of nasal patency and nasal physiology in rhinitis. J Allergy Clin Immunol. 2005;115(3. Suppl 1):S442–59. 47. Panagou P, Loukides S, Tsipra S, Syrigou K, Anastasakis C, Kalogeropoulos N.  Evaluation of nasal patency: comparison of patient and clinician assessments with rhinomanometry. Acta Otolaryngol. 1998;118:847–51. 48. Oluwole M, Gardiner Q, White PS. The naso-oral index: a more valid measure than peak flow rate? Clin Otolaryngol. 1997;22:346–9. 49. Hanif J, Eccles R, Jawad SS. Use of a portable spirometer for studies on the nasal cycle. Am J Rhinol. 2001;15:303–6. 50. Harar RP, Kalan A, Kenyon GS.  Assessing the reproducibility of nasal spirometry parameters in the measurement of nasal patency. Rhinology. 2001;39:211–4. 51. Frølund L, Madsen F, Mygind N, Nielsen NH, Svendsen UG, Weeke B. Comparison between different techniques for measuring nasal patency in a group of unselected patients. Acta Otolaryngol. 1987;104:175–9.

91 5 2. Malm L. Measurement of nasal patency. Allergy. 1997;52:19–23. 53. Wihl JA, Malm L. Rhinomanometry and nasal peak expiratory and inspiratory flow rate. Ann Allergy. 1988;61:50–5. 54. Fodil R, Brugel-Ribere L, Croce C, Sbirleau-Apiou G, Larger C, Papon JF, et  al. Inspiratory flow in the nose: a model coupling flow and vasoerectile tissue distensibility. J Appl Physiol. 2005;98:288–95. 55. Phagoo SB, Watson RA, Pride NB. Use of nasal peak flow to assess nasal patency. Allergy. 1997;52:901–8. 56. Hooper RG. Forced inspiratory nasal flow-volume curves: a simple test of nasal airflow. Mayo Clin Proc. 2001;76:990–4. 57. Morrissey MS, Alun-Jones T, Hill J. The relationship of peak inspiratory airflow to subjective airflow in the nose. Clin Otolaryngol. 1990;15:447–51. 58. Prescott CA, Prescott KE.  Peak nasal inspiratory flow measurement: an investigation in children. Int J Pediatr Otorhinolaryngol. 1995;32:137–41.

Clinical Assessment of Nasal Airway Obstruction

11

Ethem Sahin, Burak Çakır, and Klaus Vogt

11.1 Introduction

while superficially the overlying mucosa forms the second layer. Environmental and intrinsic conditions both alter nasal For the evaluation of nasal airway obstruction physical resistance. Variables reducing resistance consist of sympaexamination, anterior rhinoscopy, laboratory workup, imag- thomimetics, atrophic rhinitis, exercise, rebreathing, along ing studies, and rhinomanometric studies may be required. with erect posture [3]. Exercise leads to sympathetic vasoLaboratory workup may consist of counts of neutrophil constriction and shrinkage of the ala nasi, dilating the nasal investigating infectious diseases, eosinophil for allergy-­ cavities [1]. Infectious rhinitis, vasomotor rhinitis, allergic related disorders, and mast cell in food allergy. Imaging rhinitis, supine posture, hyperventilation, cold air, aspirin, workup contains computed tomography (CT) and magnetic and alcohol increase nasal resistance [6]. resonance imaging. Physically based studies involve rhinoThe vestibule acts as the initial area of nasal resistance. It manometry and acoustic rhinometry (AR) techniques [1]. is made up of compliant walls, which are likely to collapse from the negative pressures that are produced in inspiration. The nasal vestibule is actually called as the external nasal 11.2 Nasal Resistance valve. Research has demonstrated that an airflow rate of 30  L/min or higher can result in the collapse of the nasal Nasal resistance is responsible for more than 50% of the resis- airway during inspiration in this region. Laterally, the vestitance of the total airway [2]. The nasal cavity is designed like bule is mainly maintained by the alar cartilage and musculotwo parallel resistors [3, 4]. The nasal vestibule, nasal valve, and fibrous attachments. Though the vestibule tends to collapse nasal cavum are the three components that form the resistance in inspiration, the patency of the nasal passage is maintained in the nose [2]. The nasal valve is the main restricting part of the by the work of the dilator naris muscles. While in expiration, airflow, and is outlined by the inferior border of the upper lateral vestibule dilates with the positive pressure [3]. cartilages intersecting the caudal part of the inferior turbinates A significant region for resistance takes place at the caubeside the septum [2]. The angle between the septum and the dal border of the inferior turbinate within the access to the upper lateral cartilage is 10–15° [5], which may vary due to pyriform aperture. This critical region is referred to as the ethnic differences. The nasal valve is usually located less than internal nasal valve. Overall, the nasal valve area involves 2 cm distal in the nasal passageway, approximately 1.3 cm from the inferior border of the upper lateral cartilage, the head of the naris. The average cross-sectional area is 0.73 cm2 [2]. the inferior turbinate, the floor of the nose, the caudal sepNasal resistance is made up of two layers: the deeper tum, the frontal process of the maxilla, the pyriform aperture, layer consists of underlying bone, cartilage, and muscle, and the lateral fibrofatty tissue and forms the narrowest portion of the airway [3, 4]. It should be emphasized that the terms “external valve” and E. Sahin (*) “internal valve” are acceptable only if they are used within an Department of Otorhinolaryngology, Bayindir Içerenköy Hospital, anatomical context. From the functional point of view, only Istanbul, Turkey e-mail: [email protected] one nasal valve is existing as the entire complex of elastic structures at the nasal entrance. Recent research and development of B. Çakır Department of Otorhinolaryngology, Beykent University, nasal airway function tests are directed on quantifying the relaİstanbul, Turkey tion between nasal air stream and nasal valve movement. K. Vogt Facial nerve paralysis can cause a loss of active contraction Faculty of Medicine, Centre of Experimental Surgery, University and contribute to airway obstruction. In suspected facial nerve of Latvia, Riga, Latvia

© Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_11

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damage, the activity of the alae nasi muscle may be tested [7]. The loss of innervation can result in alar collapse even in quiet respiration. The voluntary flaring of the naris has long been associated with a potential 20% diminishment in the resistance, demonstrating the role of facial nerve in the nasal resistance [3]. The active contribution of the dilator naris happens in the course of exercise, minimizing airway resistance [8].

R=

8hi pr 4

11.3 Fluid Mechanics of Nasal Airflow Understanding the fluid dynamics of the nose as a part of nasal physiology means first to understand some basic facts: 1. The nose is an irregular rigid streaming body with elastic or movable compartments on both ends, that is, the nasal valve and the pharynx. 2. The timeline of pressure and flow is representing an irregular wave as in the overall airway. The air stream is almost unsteady, what means that it is quickly changing the speed as well as the direction. It follows that these parameters can be measured at any time but not simply calculated or predicted. 3. The nasal airstream is always in part turbulent and laminar, which can easily be shown by computational fluid dynamics (CFD). The relation between laminar and turbulent parts is changing during one breath. Therefore, the nasal airstream cannot be generally described by a simple formula. 4. Measurements of pressure and flow through the nose are integrating the airway between the anterior and posterior end, while a determination of laminar and turbulent parts of the airflow within the nose and local variations inside the nasal cavity can only be determined by CFD (Fig. 11.1).

r = 0.5, R = 16 !!

r = 1, R = 1

Fig. 11.2  The law of Hagen–Poiseuille (Courtesy of Klaus Vogt)

To better understand the relations between form and resistance of the nasal air channel, one of the basic laws in fluid dynamics is very helpful. The law of Hagen–Poiseuille is valid for the resistance of round tubes, which means that in a tube, the resistance R increases linear with the viscosity of the fluid and the length of the tube but with the 4 power of the tube radius. Reducing the radius to the half leads to a 16-fold increase of resistance! (Fig. 11.2). r = 0.5, R = 16 !!



The law applies also as an approximation for irregular cross-section areas as we find in the nose. It is also responsible for the fact, that the human eye cannot estimate the consequences of a narrowed airway as for instance also in the larynx or trachea. Also, a linear correlation does not exist between the results of acoustic rhinometry and rhinomanometry.

11.4 Assessment of Nasal Obstruction 11.4.1 History Patient background and assessment of signs and symptoms along with physical examination is the basis of the diagnosis of nasal obstruction. This history includes the characteristics of nasal obstruction/congestion; the occurrence of other symptoms of rhinosinusitis, like postnasal discharge, itching, sneezing, and ocular symptoms; associated signs, like pain, in the face and head, lack of smell sensation; as well as related data (length of the symptoms, pattern in time, and triggering events) [9]. The causes of nasal obstruction are listed below [2]:

Fig. 11.1  Typical nasal breathing curve (Courtesy of Klaus Vogt)

–– –– –– ––

Deviation of the nasal septum Turbinate hypertrophy Rhinoplasty Collapse of the nasal valve

11  Clinical Assessment of Nasal Airway Obstruction

–– –– –– –– –– –– –– –– ––

Choanal atresia Neoplasm Allergic rhinitis Polyposis Sinusitis Vasomotor rhinitis Rhinitis medicamentosa Septal perforation Septal hematoma

Mucosal vasodilation due to histamine discharge causes nasal congestion. Inflammation and discharge as a result of sinusitis can lead to stuffed nose. Deviation of the septum is a frequent source of blockage. The size of turbinates is crucial due to the fact that 50% of the airflow occurs in the middle segment of the air passage. Turbinates, which are alongside a perforated nasal septum, possibly get hypertrophied due to the turbulence of air in the nasal passage, leading to an additional airway resistance. Valvular collapse secondary to lack of cartilaginous reinforcement can result in nasal blockage. Moreover, rhinoplasty can be an important factor in iatrogenic nasal obstruction [1].

11.4.2 Rhinoscopy and Endoscopic Evaluation Anterior rhinoscopy is a procedure that can be easily done using an otoscope or a nasal speculum and headlight, nevertheless, it gives inadequate information for diagnosis. It may be suitable in extreme cases or significant alterations appear in the condition of the patient [10, 11]. A basic assessment of the degree of nasal obstruction may be possible by having the patient exhale air from the nasal passage to a cold metal. Definitive diagnosis should be made by a specialist via endoscopic examination [12]. When chronic or persistent rhinosinusitis with or without polyps is diagnosed, follow-up evaluation is required after 4 weeks of therapy [9]. The outcomes of endoscopic assessments may be quantified with different rating scales, which consist of numeric ratings of edema, discharge/rhinorrhea, polyps, adhesions, or scars as well as crusting [13]. For instance, a scale for staging polyps may be 0  =  none; 1  =  within middle meatus; 2  =  outside middle meatus yet not totally obstructing the nose; and 3 = total obstruction [9, 13].

11.4.3 Imaging Obtaining routine CT scans and MRI in order to evaluate nasal blockage is not justified, though these imaging techniques are occasionally recommended for challenging cases, like the suspicion of a neoplasia [12]. CT scan-related staging may not quite correlate with symptoms of the disease [14].

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MRI is often extra sensitive for the assessment of diseases of the sinus mucosa. Incidental information of abnormal mucosal alterations in patients having MRI for non-rhinologic conditions is actually mentioned in 31.7–55% of patients [15].

11.4.4 Objective Tests for Nasal Patency Nasal blockage is a subjective discomfort arising from physiologic and pathological alterations, which are not foreseen. If the side difference of nasal resistance between two sides is  0.05).

Nasal sIgE detection or positivity of NAPT (or both), when a generalised allergic reaction is absent, is diagnostic of LAR. In the interpretation of tests which appear negative for LAR, an important caveat relates to the fact that sIgE levels in AR and LAR are very low; hence they may be undetectable with the methods currently in use, thus producing a false negative. Nasal lavage has the advantage of being a non-­ invasive way to study cellular composition, inflammatory signals, and other markers of immunological involvement. The technique of quantifying sIgE levels in the fluid obtained from nasal lavage has value in the detection of local sensitisation in ordinary exposure as well as following NAPT.  It is, however, challenging to carry out when the patient is a young child. The test, whilst highly specific, has a low sensitivity—only 22–40% [6, 7]. An assessment is required as to what causes the relative insensitivity: overdilution, response to HDM that is not immunologically specific, or other factors may play a role. NAPT-S, a variant of NAPT wherein just one airborne allergen is utilised, is of great assistance in cases of LAR [6, 7, 16, 17], being more sensitive than nasal sIgE, tryptase or ECP quantification [6–9].

40.5.4 Local IgE Production Associated with Nasal Polyps Nasal polyps are generated by a chronic inflammatory reaction involving the sinonasal mucosa, the cause of which is unknown. Recent findings support the idea that Staphylococcus aureus causes alterations in the pattern of disease within the airways by provoking the production within polyps of IgE against superantigens associated with S. aureus [23] by various clonal lines as well as against allergens found in the environment [24]. The idea that multiple clones produce IgE that targets a number of different airborne and non-airborne allergens differs from the models proposed for how IgE is produced in LAR, which state that specific IgE secretion in response to airborne allergen of a particular type sets in motion a response involving B cells, mast cells, and eosinophils, a response where the total IgE level in the nose remains low. How this translates into clinical differences remains to be clarified.

40.5.5 Local IgE Production Associated with Asthma There are many reasons to posit an overlap between allergic and non-allergic asthma subtypes. Lung tissue obtained in cases of both types reveals elevated levels of B cells with heavy-chain class-switch recombinations [25] and elevated levels of mRNA production for interleukins 4 and 5 [26].

40.7 Testing for Local Allergic Rhinitis The confinement of IgE to particular locales as a concept began in the 1970s [27, 28], with some revisiting of the idea thereafter [29–32]. The term “entropy” was coined in 2003 to highlight the difference from atopy [28], but the terminology of Rondon et al. (“local allergic rhinitis”) [8] is more apt. They reviewed 3860 patients in attendance at an allergy clinic over a 1-year period and picked out 452 for detailed evaluation of rhinitis [2]. Some 428  in total completed the survey and 24 were left out due to nasal hyperreactivity. Diagnostic rates for LAR, AR and NAR were 25.7%, 63.1% and 11.2%, respectively. The diagnostic criteria for LAR were: negative cutaneous testing, negative serum sIgE level, but positive NAPT. LAR had begun during childhood for over a third of LAR patients. For AR and LAR, in each case the main allergen implicated was HDM—60% and 54%, respectively. The inescapable fact is that LAR is frequent amongst rhinitis sufferers. Failure to consider LAR would entail many patients with an allergy receiving false reassurance that no allergy exists. Direct sampling of the mucosal surfaces of the nose and sinuses offers the opportunity to test for sIgE in situ as a step to diagnosing LAR. It was Ohashi and colleagues who first advocated obtaining biopsy specimens in the quantification of localised sIgE [33]. Amongst patients clinically evaluated

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as having AR, t-RAST (tissue-specific radioallergosorbent testing) for sIgE was positive universally. By comparison, cutaneous testing with serum IgE titres was positive 67% of the time and NAPT 25% of the time. Ahn and colleagues found IgE to both mycological and non-mycological allergens in inferior turbinate-derived biopsy tissue obtained from cases of allergic fungal rhinosinusitis. Subepithelial IgE levels exceeded those found within the mucosa [34]. MBB with a standard brush used for cytology is a minimally invasive method to obtain both mucus and epithelial tissues, which can be undertaken in a clinic or doctor’s office setting using only local anaesthesia. The samples thus obtained are homogenised, subjected to cell lysis, and the IgE extracted from cellular membranes using a specially designed technique. The material thus prepared is then suitable for use with ELISA or component-resolved diagnosis, which are commercially produced [35]. A 2012 study looked at the use of MBB to evaluate sIgE to nine frequent aeroallergens in a cohort of patients clinically diagnosed with AR and who had shown positivity to a minimum of two such antigens on cutaneous testing [36]. 75% of the group as a whole produced a positive MBB test, and four patients showed positivity for antigens that had not shown up on cutaneous testing. A negative MBB test for an antigen correlated with smaller wheal diameter on cutaneous tests and vice versa. A further method for the detection of IgE within the mucosal lining of the nose was advocated by Marcucci and Sensi [30]. In this method, a paper-based strip contains bound antigens at two different points along its length and is coated with a permeable membrane that prevents nasal mucus adhering to the paper. It is placed within the posterior tract in the internal ostium and left for 10  min. After colorimetric analysis, the result can be interpreted by reading off from plotted values to a scale going from negative (“0”) to strongly positive (“4”). A newly released study has compared how NAPT and nasal IgE testing compare in children with known rhinitis, at the period when Alternaria spores are airborne. Both NAPT and nasal sIgE against Alternaria tests were simultaneously positive in around 70% of cases, whilst positive cutaneous testing that correlated with NAPT existed in 27% of cases. Both results were at the high level of statistical significance (p  200 mL per side) intranasally [33]. Nonsedating H1 antihistamines are not as successful in NAR, compared with allergic rhinitis, so they are not recommended for NAR treatment [50]. Older, first generation H1 antihistamines (e.g., chlorpheniramine) have anticholinergic properties which may be useful for some subjects with resistant and bothersome postnasal drip and/or anterior rhinorrhea despite the use of the aforementioned therapies. However, one should keep in mind that these medications are sedating and preferably be dosed at night. Botulinum toxin type A (BTA) is a neurotoxin. BTA binds to extracellular glycoprotein structures on cholinergic nerve terminals and blocks intracellular acetylcholine (ACH) release. ACH acts as a neurotransmitter for the innervation of muscles and different glands. Impeding the secretion of ACH leads to a decline in gland secretion [51]. In NAR, double-­blind, placebo-controlled clinical studies, using BTA injections or BTA administered with soaked sponges, have been demonstrated to decrease congestion, sneezing, rhinorrhea, and itching [52, 53]. The effect of the treatment lasted 2–3 months. Adverse events such as epistaxis or nasal crusting were infrequent. More studies are needed to investigate the effectiveness of BTA on NAR symptoms. Surgical Treatment Surgical treatment in NAR is usually preferred for subjects with recalcitrant symptoms not responding to standard therapies, such as topical nasal steroids in combination with topical antihistamines and/or decongestants and/or ipratropium bromide [54]. Surgical reduction of the inferior turbinates is a frequently performed procedure in subjects that have nasal congestion. In a recent study, it has been shown that surgical reduction of the inferior turbinates provides an improvement in nasal airflow with a reduction in obstructive symptoms in the short term, but its efficacy tended to decline within 3 years [55]. Other surgical procedures include vidian neurectomy and sphenopalatine ganglion block. A systematic review to compare open vidian neurectomy with the endoscopic tech-

A. Sahin-Yilmaz et al.

niques stated that rhinorrhea and nasal obstruction were shown to recover after endoscopic vidian neurectomy and the benefits were maintained for numerous years after surgery. Endoscopic vidian neurectomy is a well-tolerated, secure, and efficient procedure for many patients [54, 56]. Long-term benefits of this surgical procedure remain to be elucidated.

41.4 Nonallergic Rhinitis with Eosinophilia/Local Allergic Rhinitis Nonallergic rhinitis with eosinophilia syndrome (NARES) can be described as an eosinophilic inflammation of the nasal mucosa without the presence of AR or other nasal problems. The complaints are like AR (nasal congestion, sneezing, rhinorrhea, ocular symptoms); however skin testing is not positive [57]. NARES was originally defined by the existence of more than 20% eosinophils in smears taken from the nose [58]. However, there is currently no consensus on the eosinophilic threshold required for diagnosis, because any amount from greater than 5% to greater than 20% has been reported to indicate this condition [4]. Although the over activation of mast cells as a part of chronic inflammation is suggested to play a role in the development of NARES, the exact pathophysiology is unknown. Subjects can develop nasal polyposis, sensitivity to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), and bronchial hyperreactivity. The term NARES currently is less favored in the literature since questions have raised regarding whether this is a distinct condition or whether it mostly overlaps with other conditions such as local allergic rhinitis [1]. Local allergic rhinitis (LAR) has been proposed to be a separate rhinitis endotype with symptoms similar to AR related to local allergen-specific IgE, but with no proof of systemic specific IgE. In a recent study, ratio of development of systemic atopy was similar in LAR patients and healthy controls, which suggests that LAR is well differentiated from AR [59]. Nevertheless, others have suggested that nasal IgE versus allergens is a not an exclusive phenomenon, as they may similarly be detected in nonallergic rhinitis and in healthy individuals [60]. The features of LAR are a local Th2 inflammatory reaction which involves production of nasal specific IgE and gathering of eosinophils, basophils, mast cells, and CD3+/ CD4+ T cells [61]. Patients with LAR respond to intranasal steroids and oral antihistamines. More research is needed to assess mechanisms and the clinical and immunological differences between NARES and LAR.

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41  Nonallergic Rhinitis

41.5 Drug-Induced Rhinitis • Rhinitis medicamentosa Rhinitis medicamentosa is provoked by overuse of topical decongestants. Classically, the physical examination reveals erythematous (beefy red) and congested nasal mucosa with areas of punctate bleeding caused by tissue friability [62]. Histologic changes consistent with rhinitis medicamentosa are as follows: mucociliary loss, squamous cell metaplasia, epithelial edema, epithelial cell denudation, hyperplasia of goblet cells, increased expression of the epidermal growth factor receptor, and inflammatory cell infiltration [63]. Nasal congestion is a result of rebound swelling of the mucosa after the effects of the decongestant drugs have disappeared. The mechanisms underlying this condition are suggested to be due to reduced development of endogenous norepinephrine through negative feedback. This results in edema formation by altering vasomotor tone and vascular permeability through increased parasympathetic activity [64]. Treatment of rhinitis medicamentosa involves stopping the usage of nasal decongestants so that the damaged mucosa will heal. Topical corticosteroids could be preferred to lessen rebound edema of the nasal mucosa [65]. • Antihypertensive and cardiovascular agents Drug-induced rhinitis may be observed following the use of sympatholytic drugs like alpha-adrenergic and beta-­ adrenergic antagonists, like clonidine, guanethidine, doxazosin, and methyldopa. Other antihypertensive drugs (e.g., beta-blockers, ACE inhibitors, calcium channel blockers) may induce rhinitis. Although some assumptions can be made related to underlying mechanisms causing rhinitis for some of these agents (e.g., ACE inhibitors resulting in increased release of bradykinin, which is a potent vasodilator), the pathophysiologic basis remains to be investigated [4].

The pathogenic mechanism is thought to be the blockage of cyclooxygenase 1, shifting the metabolism of arachidonic acid to the lipoxygenase pathway, resulting in reduced production of prostaglandin E2 and increased cysteinyl leukotriene release precipitating local inflammation [67]. • Oral contraceptive drugs It has been suggested that oral contraceptives and other estrogens, and even cyclical premenstrual hormones can cause rhinitis. The nasal respiratory epithelium is suggested to be an ovarian steroid target along with the vaginal cells. The maturation index of the nasal respiratory epithelium has been shown to change according to the variation of the ovarian steroids during the menstrual cycle and the use of oral contraceptives [68]. Estrogen-beta receptors were shown in the nasal mucosal glands and a positive association between the number of estrogen-beta positive cells and symptoms was demonstrated [69]. Estrogens have been suggested to effect neuronal plasticity and the neuronal conduction in the olfactory system in a study of postmenopausal women on hormone replacement therapy [70]. Whether this condition can be observed clinically has been a matter of debate in the literature. No discernible effect of oral contraceptives or hormone replacement drugs upon nasal physiology has been shown in two different studies [71, 72]. • Other drugs Other drug classes that could cause rhinitis are phosphodiesterase-5 selective inhibitors like sildenafil, tadalafil, and vardenafil, which act through their vasodilating properties. This group of medications is thought to affect the erectile tissue of the nasal turbinates causing nasal congestion [4].

41.6 Hormonal Rhinitis

• Aspirin/nonsteroidal anti-inflammatory drugs Ingestion of aspirin and other nonsteroidal anti-­ inflammatory drugs may cause local rhinitis. More recently, for those patients in whom the chronic inflammatory respiratory disease exacerbates by aspirin or other NSAIDs, the term aspirin-exacerbated respiratory disease (AERD) is used. In patients with AERD, use of aspirin or other NSAID may induce nasal congestion and watery rhinorrhea within 30–120  min, sometimes followed by difficulty in breathing and quickly progressing bronchial obstruction [66].

Hormonal rhinitis includes two phenotypes, i.e., rhinitis of pregnancy and menstrual cycle-associated rhinitis [19]. Rhinitis of pregnancy is a common condition. It affects one in five pregnant women and is more prevalent among smokers. Pregnancy rhinitis may cause sleep apnea, which consecutively may adversely affect the outcome of pregnancy [73]. Rhinitis of pregnancy typically begins in the last 6 weeks of pregnancy and settles spontaneously within 2  weeks following birth [74]. Estrogen concentrations are usually in accordance with the severity of symptoms. They are

A. Sahin-Yilmaz et al.

360

abundant in the second trimester. One study, however, has shown that rhinosinusitis-specific quality of life is lower in the third trimester [73]. A raised level of estrogen is suggested to cause nasal congestion by vascular engorgement. Additionally, pregnancy hormones stimulate nasal mucous gland hyperactivity, and more rhinorrhea. Nevertheless, there is no direct proof that these hormones contribute directly to rhinitis in pregnant women. Hormonal rhinitis has also been associated with acromegaly and hypothyroidism. Treatment of rhinitis in pregnancy consists mainly of information, physiological measures, and nasal saline washings. Elevating head end of the bed, physical exercises, using nasal saline, and nasal alar dilation may improve nasal breathing [75]. Topical treatment is usually favored to systemic medications. In a placebo-controlled clinical trial performed to assess the decongestive effect of phenylpropanolamine twice daily for 7 days, it has been shown to be an efficient and safe treatment in pregnancy rhinitis [76]. However, phenylpropanolamine has been removed from the US market because an association was found between phenylpropanolamine and hemorrhagic stroke in man.

41.7 Atrophic Rhinitis This is a chronic nasal disease characterized by dense viscid secretions and crust formation in the nasal cavity, formed due to gradual atrophy of the nasal mucosa and the turbinates. The underlying pathophysiology is unclear but it is either caused by a lack of mucus, thereby facilitating bacterial growth, leading to mucosal colonization (usually with Klebsiella ozaenae, Staphylococcus aureus, Proteus mirabilis, and Escherichia coli) or, vice versa, microbial colonization may be the primary cause of this condition [4]. The common symptoms are fetor, ozena, crusting, nasal stuffiness, epistaxis, anosmia and/or cacosmia, and secondary infections. Atrophic rhinitis is mainly observed in young or middle-aged Asian, Hispanic, and African-American female adults [77]. Secondary atrophic rhinitis has similar symptoms, but is due to extensive surgery of tissues, trauma, or chronic granulomatous disorders. Diagnostic criteria are as follows: recurrent epistaxis or episodic anosmia, or nasal purulence, crusting, and chronic upper airway inflammatory diseases such as sarcoidosis and Wegener’s granulomatosis or a history of more than one sinus surgery [78]. Treatment of atrophic rhinitis is mainly conservative using nasal irrigations and nasal drops (containing glucose-­glycerin or liquid paraffin), antibiotics, and vasodilators. The goals of surgical inventions are reduction in the volume of the nasal cavities, promoting regeneration of healthy mucosa, increasing lubrication, and improving the

vascularity. A Cochrane database review showed no evidence on the long-­term results of different management modalities for atrophic rhinitis [77]. Additional studies with a longer follow-up should be planned for this chronic problem.

41.8 Senile Rhinitis Senile rhinitis can be defined as rhinitis of the population above 65 years. AR is observed in approximately 12% of the geriatric population and is becoming gradually more recognized. It seems that NAR increases with age, and the highest prevalence is seen in the elderly [19]. Structural changes in the elderly population include loss of nasal tip support that leads to a dropped nasal tip and septal cartilage and nasal columella retraction that causes changes in the nasal cavity. A decrease in the nasal airflow is not unusual and all these changes account for the symptoms of nasal congestion often found in older adults. The mucosal epithelium becomes atrophic and dry. A decrease in mucosal blood flow has been found with increasing age [79]. The viscoelastic properties of nasal mucus change and thick mucus mixed with impaired mucociliary function leads to the rhinitis symptoms of chronic postnasal drainage, nasal drainage, and cough [80]. Aging is associated with decreases in olfaction, with the greatest decline occurring usually after the seventh decade [81]. Alterations in immune cell function results in decreases in T-cell and B-cell functions in the elderly [82, 83]. Evidence on the suggested treatment methods for senile rhinitis is scarce. Intranasal steroids, topical antihistamines, and nasal lavage may be recommended. Use of oral decongestants in elderly patients is not advised due to concomitant medical problems such as hypertension and cardiac disease. Ipratropium bromide is best used when the key symptom is rhinorrhea as in cold air-induced rhinitis. Radiofrequency turbinoplasty may be considered for treating some NAR symptoms such as nasal obstruction and rhinorrhea in the elderly.

41.9 R  hinitis Due to Indoor and Outdoor Pollutants Environmental nonallergic rhinitis a condition triggered by ambient physical or chemical exposures (i.e., cold dry air, second-hand tobacco smoke, wood smoke, fragrances and cleaning products, and industrial chemicals) in individuals without evidence of a typical allergic (immunoglobulin E-mediated) mechanism. The state of exaggerated nasal reflexes underlying this condition is referred to as nonspecific nasal hyperreactivity [84, 85].

41  Nonallergic Rhinitis

Irritant air pollutants include, in addition to “criteria air pollutants” (ozone, nitrogen oxides, sulfur dioxide, and particulate matter), a variety of industrial chemicals, combustion products (smokes and fumes), cleaning chemicals, and volatiles evolved by building materials and/or microbial growth [86]. Nasal obstruction induced by these triggers potentially occurs through mast cell degranulation, central neurogenic (e.g., parasympathetic) reflexes, peripheral neurogenic reflexes, or epithelial cell activation. Avoidance of these triggers can be challenging for some individuals, and as a result the condition has attracted significant attention in pharmaceutical groups.

41.10 Summary Nonallergic rhinitis is a challenging disease for the clinician since it is bothersome to make a distinction between its phenotypes and symptom triggers and decide on the type of treatment. Avoidance of triggers is a challenge for the patients, so is the success of treatment strategies. Topical corticosteroids are first-line drugs. The use of azelastine has also been found to be effective. Fluticasone propionate and azelastine is a promising combination for improved symptom relief. Better conducted randomized controlled studies are mandatory to improve our understanding of the efficacy of capsaicin in NAR. Surgical options for subjects refractory to medical treatment are unfortunately inadequate.

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Part V Nasal Polyposis

Epidemiology of Nasal Polyposis

42

Erkan Esen, Adin Selçuk, and Desiderio Passali

42.1 Introduction Nasal polyps (NP) are benign, edematous masses growing into nasal cavity that could have multiple etiological factors [1–5]. Basic etiological factor for polyp formation is chronic inflammatory change and thus stromal nasal and paranasal mucosa edema [6]. All theories about NP formation try to explain the edema formation. Edema and mucosal inflammation may originate from trauma; bacterial, viral, or fungal infections; environmental irritants; or allergens [7]. The prevalence of NP in the general population is unclear. It varies from 0.2% to 5.6%. Different diagnostic measurements and criteria may be responsible for this wide range [1–5]. Additionally, age, gender, and such demographical factors affect the variability. Ethnic and genetic factors should also be taken into consideration. The prevalence of NP shows a wide range according to etiology. The most important data on the epidemiology of NP are obtained from NP etiology studies. For these reasons, in this chapter, epidemiological data are presented parallel to the etiological reasons and hypotheses of NP.  The main hypotheses that lead to the development of NP will be discussed below with the current incidence and prevalence rates.

42.2 Genetics There may be hereditary factors for NP but there is limited knowledge in this area. However, we have some evidence for genetic inheritance. Studies reported that up to 14% of

E. Esen (*) · A. Selçuk Department of Otorhinolaryngology, University of Health Sciences, Kocaeli Derince Training and Research Hospital, Istanbul, Turkey D. Passali Medical Faculty, Department of Otorhinolaryngology—Head and Neck Surgery, University of Siena, Siena, Italy

patients with NP have a family history [8]. A link has been indicated that NP and asthma have an association with HLA-­ A1B8 and HLA-A74 genes [9, 10]. Monozygotic twin studies tried to describe genetic pathway for NP. Both or none of identical twins showed NP with asthma and aspirin intolerance [11, 12]. In terms of familiar association, studies have revealed the presence of family history in patients with NP. In a report, 52% of patients with NP showed family history in the last three generations [13]. Another study documented a family history of patients with NP over 14% [14]. NP, most likely has a genetic predisposition, but there is no definite inheritance model. Gene and environment communication is likely at work [15]. In some genetically transmitted disorders the formation of NP is a disease characteristic symptom, such as cystic fibrosis, primary ciliary dyskinesia, and Young’s syndrome. The association of NP with cystic fibrosis is clearly reported. Studies documented NP prevalence as 10–37% of fibrotic patients [11, 16–18]. Transmembrane conductance regulator (CFTR) gene mutations occur in cystic fibrosis as autosomal recessive disorder. These CFTR gene mutations create intestine, liver, lung, and exocrine gland changes by affecting chloride ion channels [11]. Children younger than 16 years old, who have NP, should be investigated for cystic fibrosis. NP is also related to chronic dyskinetic cilia syndrome, also known as Kartagener’s syndrome, in these cases neutrophils are the predominant cells reveled in nasal mucosa. Primary ciliary dyskinesia has very different genetic circumstances, with an estimated incidence of 0.02% [19, 20]. Kartagener’s syndrome is inherited as an autosomal recessive disease and it is characterized by chronic sinusitis, bronchiectasis, and situs inversus (complete reversal of internal organs). This syndrome affects cilia; there are defects in dynein arms of cilia and microtubule transposition anomalies [21]. The ciliary abnormality involves the entire body, including the respiratory and genital tract.

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Both Kartagener’s syndrome and cystic fibrosis patients have sensitivity to Pseudomonas aeruginosa infection. So antibiotic therapy should be taken into consideration against this pathogen [22, 23]. Young’s syndrome is another disorder consisting NP, recurrent respiratory disease, obstructive azoospermia [24]. Young’s syndrome is different from cystic fibrosis and primary ciliary dyskinesia in way of showing normal sweat chloride test. Ciliary function and structures are normal such as normal sperm tails and normal tracheal biopsies. Spermatogenesis is normal but there is a male infertility of about 7.4%, because of epididymis blockage with concentrated secretions [25].

42.3 Age and Gender The general consensus is that the incidence of NP increases with age and it is more common in male population [26, 27]. It has been suggested that there is a 2:1 male to female preponderance at least [26]. Recently, Hulse et al. published that male-to-female ratio is changing from 1.3 to 2.2 [28]. NP largely affects adults and mostly presents in patients older than second decades. It usually occurs in middle age, generally between the fourth and fifth decades [29]. NP appears rarely among pediatric population that the prevalence is estimated to be 0.1% [11]. NP is infrequent in children under 10 and may be associated with cystic fibrosis or antrochoanal polyps [11] (Figs. 42.1, 42.2, 42.3, 42.4).

Fig. 42.2  Coronal CT view of right antrochoanal polyp (courtesy of Fazilet Altin)

It has been implied that the incidence of NP increases with age. Settipane et al. published that the frequency of disease achieves a peak in patients who are over 50 years of age [30]. Also he reported asthmatic persons over 40  years of age have about four times tendency to have NP. Johansson et  al. indicate that individuals with NP over 60  years of age have a prevalence of 5%; on the other hand, it is 1% in persons younger than 40  years of age [4]. Larsen et  al. reported much similar results in Danish population who have NP. They observed that NP patients are between 40 and 60 years of age. The mean age diagnosis was 51 in males and 49 in females [26]. Klossek et al. also reported similar data. They published that NP prevalence is 1.22% between 18 and 24 years of age, and 2.47% in 65 years of age [2].

42.4 Allergy

Fig. 42.1  Right antrochoanal polyp (courtesy of Fazilet Altin)

Even if in the past nasal allergy was considered to be a key pathology in the NP etiology, today, the role of allergens causing polyps is controversial; in fact several patients with nasal polyps have low seric IgE levels and/or negative skin tests. The connection between allergy and nasal polyp has not been efficiently explained in literature. NP prevalence in patients with allergic rhinitis is predicted to be between 1.5% [30] and 1.7% [31], a ratio similar to the general population one. Contrarily, other studies reported a connection with allergy, regarding the relationship between positive skin

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42  Epidemiology of Nasal Polyposis

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b

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Fig. 42.3 (a–c) Endoscopic view of antrochoanal polyp (courtesy of Fazilet Altin)

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Fig. 42.4 (a, b) Operation specimen of antrochoanal polyp (courtesy of Fazilet Altin)

tests and NP. Different authors published higher frequency of allergic symptoms appearance and food allergy in patients with NP than in the general population. Rugina et al. carried out a multicenter study, and found that 32.5% of the patients with NP have positive skin tests [13]. Settipane reported 55% positive skin test rate in patients with NP [30]. Klossek recorded 26.1% positive skin tests in patients with NP [2]. Moreover, Bonfils et al. published two studies founding positive phadiatop test results of 19.5% and 16.2% in patients with NP [32]. Sin et al. showed the presence of allergy in patients with NP using skin tests and demonstrating serum-specific IgE levels. With respect to the two tests, 45.2% of the cases were classified as allergic, while the skin tests were positive in 66.3% of the patients [33]. On the other hand, Pastorello et  al. conducted a study, and they determined specific IgE in 38% of the serum and in 32% of the nasal secretions of nasal polypectomy-performed patients [34].

It has been suggested that there may be local IgE secretion without increasing level in serum or in the derma to be detected by skin tests [35]. A meta-analysis reviewed nine studies with specific IgE in serum levels and nasal mucosa. Nineteen percent of the patients’ have positive nasal IgE, but negative serum IE; so we can consider that a percentage of patients with NP may show local allergy [36].

42.5 Asthma Another associated factor is asthma. The relationship between nasal polyp and asthma can be defined from two different aspects: asthma patients who develop polyps, and patients diagnosed with NP who develop asthma after that. A number of studies are cited below demonstrating strong association between these two clinical entities, while disputing the association between atopy and polyps.

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Settipane reported that, on about 2000 patient samples, NP were more prevalent in patients with nonallergic asthma than with allergic asthma (5–13%) [11]. Another large cohort study conducted by Grigoeras et al. evaluated 3,817 patients with asthma and chronic rhinitis; the incidence of NP was 4.2% in this population. The incidence of polyps’ prevalence in nonallergic asthma was 13% and allergic asthma was 2.4%. There was a correlation between NP and allergy and allergic asthma [31]. Also, there are some small group studies supporting this relationship. An epidemiological study, carried out on NP patients diagnosed by endoscopic findings, by Johansson et al. found that 30% of the patients had experienced asthma attacks or breathing difficulties before [4]. Bonfils et  al. published a study, evaluating allergy and asthma co-occurrence in patients diagnosed with NP on the basis of the endoscopic and computed tomography findings; a 48.6% incidence of asthma and a 22.8% incidence of bronchial hyperresponsiveness have been reported in these patients [32]. Bronchial hyperresponsiveness has also been reported in patients with NP. In a study patients with NP underwent methacholine challenge testing, the researchers found 35% bronchial hyperresponsiveness in those subjects [37].

42.6 Aspirin Intolerance The relationship between NP and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs intolerance is well known in daily clinical practice. In 1968, Samter described the clinical triad of bronchial asthma, aspirin sensitivity, and NP.  This “triad” of symptoms is generally referred to as “Samter’s triad” or “ASA triad.” These medications provoke an acute asthmatic response within minutes [38]. A great number of affected patients produce an acute bronchial response with rhinorrhea, nasal obstruction, facial pain, postnasal drip, and anosmia. Aspirin intolerance is seen in 5–10% of asthmatic patients and NP prevalence in these patients is higher than the general population and also higher than the nonaspirin intolerant asthmatic population. The recorded incidence of NP is changing from 36% to 95% [11, 38]. In the development of ASA triad, first, patients show chronic rhinitis symptoms. After about 5–10  years aspirin-­ induced asthma will appear. Then the symptoms evolve into NP.  The nasal polyps of ASA-triad patients present with increased edema and inflammatory infiltrate were compared to the polyp of aspirin tolerant patients [39]. NP in ASA-triad patients accompanies to severe inflammation, which is more persistent to medical and surgical treatment. The response of ASA-triad patients to surgery is usually poor, and the patients have to undergo endo-

scopic sinus surgery procedures several times. Moreover, ASA-triad patients have a considerably higher amount of symptom recurrence, and also regrowth of nasal polyps [40, 41].

42.7 Allergic Fungal Rhinosinusitis Allergic fungal rhinosinusitis (AFRS) is an old concept many times connected to chronic rhinosinusitis and is greatly related, by several authors, to NP. Safirstein first related NP with Aspergillus collected from the paranasal sinuses in 1976 [42]. The incidence of AFRS has not been well demonstrated, but about 5–10% of NP patients have AFRS [43]. It is typically young adults’ disease, with an age interval of 22 and 28 [44]. Some studies have suggested that there is an increased prevalence of AFRS in more humid climates, and lower socioeconomic status may also play a role [44]. The nature of the immune reaction is not clear but it is a simple type I hypersensitivity reaction. The existence of fungal specific IgG would display a type III reaction that could be involved in the polyps pathogenesis [45]. This may result in a circle of mucosal edema, and chronic rhinosinusitis and NP. Diagnosis can be made by clinical suspicion and intraoperative observation of eosinophilic mucin and NP. AFRS diagnosis is based on the presence of five characteristic features: type I hypersensitivity reaction, nasal polyps, paranasal sinus CT scan findings; thickened mucus (gray-brown) with calcification, eosinophilic mucus containing CharcotLeyden crystals, and positive fungal stains from sinus material. The diagnosis of AFRS should be kept in mind in every atopic patient and nasal polyps that is unrelieved by routine therapy. Culture identification, positive skin test to fungus, positive serum markers, elevated specific IgE and IgG antibodies, and biopsy staining for fungal elements would prove the existence of AFRS.

42.8 Key Points • The exact prevalence of nasal polyps is not known. In the literature, it changes between 0.2% and 5.6%, varying according to the diagnostic methods. • There is a weak association between NP and allergic rhinitis. • Large cohort studies have reported a great relationship between NP and asthma. • The incidence of NP increases with age and peaks between the fourth and fifth decades of life. It is somewhat higher in males.

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compared with that in normal subjects and in subjects with various respiratory diseases. Am Rev Respir Dis. 1984;129:161–7. 21. Sturgess JM, Thompson MW, Czegledy-Nagy E. Genetic aspects of immotile cilia syndrome. Am J Med Genet. 1986;25(1):149–60. 22. MacKay ON.  Antibiotic treatment of rhinitis and sinusitis. Am J Rhinol. 1987;1:83–5. 23. Taccetti G, Campana S, Neri AS.  Antibiotic therapy against pseudomonas aeruginosa in cystic fibrosis. J Chemother. 2008;20(2):166–9. 24. Handelsman DJ, Conway AJ, Boylan LM.  Young’s syndrome. Obstructive azoospermia and chronic sinopulmonary infections. N References Engl J Med. 1984;310(1):3–9. 25. Schanker HM, Rajfer J, Saxon A.  Recurrent respiratory dis 1. Hedman J, Kaprio J, Poussa T, Nieminen MM.  Prevalence of ease, azoospermia, and nasal polyposis. A syndrome that mimasthma, aspirin intolerance, nasal polyposis and chronic obstructive ics cystic fibrosis and immotile cilia syndrome. Arch Intern Med. pulmonary disease in a population-based study. Int J Epidemiol. 1985;145(12):2201–3. 1999;28:717–22. 26. Larsen K, Tos M.  The estimated incidence of symptomatic nasal 2. Klossek JM, Neukirch F, Pribil C, Jankowski R, Serrano E, Chanal polyps. Acta Otolaryngol. 2002;122:179–82,6. I, El Hasnaoui A. Prevalence of nasal polyposis in France: a cross-­ 27. Drake-Lee AB, Lowe D, Swanston A, Grace A. Clinical profile and sectional, case-control study. Allergy. 2005;60:233–7. recurrence of nasal polyps. J Laryngol Otol. 1984;98:783–93. 3. Cingi C, Demirbas D, Ural A.  Nasal polyposis: an overview of 28. Hulse KE, Stevens W, Tan BK, Schleimer RP. Pathogenesis of nasal differential diagnosis and treatment. Recent Patents Inflamm polyposis. Clin Exp Allergy. 2015;45:328–46. Allergy Drug Discov. 2011;5(3):241–52. 29. Fokkens W, Lund V, Mullol J.  EP3OS 2007: European position 4. Johansson L, Akerlund A, Holmberg K, Melen I, Bende paper on rhinosinusitis and nasal polyps 2007. 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Part II.  Surgical Technique 33. Sin A, Terzioglu E, Kokuludag A, Veral A, Sebik F, Karci B, Otolaryngol Head Neck Surg. 1986;94(2):147–56. Kabakci T.  Allergy as an etiologic factor in nasal polyposis. J 8. Greisner WA, Settipane GA. Hereditary factor for nasal polyps. J Investig Allergol Clin Immunol. 1997;7:234–7. Allergy Clin Immunol. 95, 1(part 2):205. 34. Pastorello EA, Incorvaia C, Riario-Sforza GG, Codecasa L, 9. Luxenburger W, Posch G, Berghold A.  HLA patterns in Menghisi V, Bianchi C.  Importance of allergic etiology in nasal patients with nasal polyposis. Eur Arch Otorhinolaryngol. polyposis. Allergy Proc. 1994;15:151–5. 2000;257:137–9. 35. Kule ZA, Deveci HS, Kule M, Habesoglu TE, Somay A, Gursel 10. Moloney JR, Oliver RTD. HLA antigens, nasal polyps and asthma. AO. The correlation of clinical measures with the histopathological Clin Otolaryngol. 1980;5:183–9. findings in nasal polyposis. ENT Updates. 2015;5(1):1–8. 11. Settipane GA. Epidemiology of nasal polyps. 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J Dis Child. 1982;136:1067–70. 43. Corey JP.  Allergic fungal sinusitis. Otolaryngol Clin North Am. 18. Cepero R, Smith RJH, Catlin FI, Bressler KL, Furuta GT, Shandera 1992;25:225–30. KC.  Cystic fibrosis–an otolaryngologic perspective. Otolaryngol 44. Wise SK, Ghegan MD, Gorham E.  Socioeconomic factors in the Head Neck Surg. 1987;97:356–60. diagnosis of allergic fungal rhinosinusitis. Otolaryngol Head Neck 19. Atzellus BA.  Disorders of ciliary motility. Hosp Pract. Surg. 2008;138:38–42. 1986;21:73–80. 45. Manning SC, Holman M. Further evidence for allergic pathophysiol 20. Rossman CM, Lee RM, Forrest JB, Newhouse MT.  Nasal ciliary ogy in allergic fungal sinusitis. Laryngoscope. 1998;108:1485–96. ultrastructure and function in patients with primary ciliary dyskinesia

• Asthma is common (20–48%) in patients with NP. This relationship increases in patients with aspirin intolerance. • The genetic-hereditary factors are held responsible for underlying possible etiology of NP but it remains to be clarified.

Pathophysiology of Chronic Rhinosinusitis with Nasal Polyps

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Fatih Boztepe, Ahmet Ural, Gaetano Paludetti, and Eugenio De Corso

43.1 Introduction Chronic rhinosinusitis (CRS) is defined the following way in the 2012 EPOS guidelines [1]: nasal and paranasal sinus inflammation lasting a minimum of 12 weeks, plus at least two of the following features: blocked nose, rhinorrhoea, pain or pressure sensation over the face, hyposmia or anosmia. According to this guideline, at a minimum, the nose should be obstructed or there must be nasal drip anteriorly or posteriorly to qualify for the diagnosis. This clinical diagnosis can then be confirmed objectively through CT scanning of the sinuses or nasal endoscopy, which also permits characterisation as chronic rhinosinusitis with or without nasal polyp formation (CRSsNP and CRSwNP, respectively). Polyps characteristically contain elevated levels of IL-5 and IL-13, produced by T-helper 2 cells, as well as histamine [2]. Through the endoscope, polyps take on a translucent, glistening appearance, with a colour between yellowishgrey and white, and are seen to contain abundant inflammatory debris of a gelatinous consistency. They arise from the mucosal linings of the nasal sinuses or the nose itself. They are particularly frequent at the ostia of the sinuses. Due to being poorly vascularised, polyps have a greyish-white appearance. It is fairly uncommon to find polyp formation confined unilaterally, despite the occurrence of a sole polyp on occasion at the middle meatus or the posterior recess of the sphenoethmoid. Polyps which form unilaterally may exhibit a difference in appearance and are a suspicious feature for inverting papilloma, fungal infection or a neoF. Boztepe (*) Department of Otorhinolaryngology, Antalya Medical Park Hospital, Antalya, Turkey A. Ural Medical Faculty, Department of Otorhinolaryngology, Bolu Abant İzzet Baysal University, Bolu, Turkey G. Paludetti · E. De Corso Agostino Gemelli Hospital Foundation, Catholic University of the Sacred Heart, Head and Neck Surgery Area, Institute of Otorhinolaryngology, Rome, Italy

plasm. Combining sinusal CT with MRI is often beneficial diagnostically [3]. A confirmation of unilaterality through imaging should make the clinician evaluate other possible diagnoses [4, 5]. The CT appearances of CRS are of bilateral, markedly thickened mucosae. Whilst polyps have similar signal attenuation to mucosa that is thickened, their outlines allow them to be distinguished. Polyps protrude with a rounded outline into the hollow region of the nose or sinus [6]. If polyps are numerous, there may be trapping of secretory matter in gaps between polyps. Secretions may appear in higher density on CT, with polyps having varying density, some areas sufficiently so to mimic widespread or localised calcification, as found in dystrophic lesions [7]. Many individuals with CRS also have other conditions. Asthma and CRSwNP commonly co-occur, but their interactions remain not fully known [8]. Research into radiological findings in asthmatic patients has shown that the mucosal lining of the sinuses in a high percentage of cases is abnormal [9, 10]. Where asthma was of a degree to require steroids in management, this finding applied to 100% of cases; 88% of mild or moderate asthmatics also had abnormal sinus mucosa [11]. GA2LEN was a study involving more than 52,000 individuals aged 18–75 attending 19 centres based in 12 countries. It concluded that CRS is strongly associated with asthma, being strongest when allergic rhinitis was also present [12]. Thirty-one per cent of CRSwNP sufferers report wheezing, and 42% difficulty breathing, the rate of asthma being 26% in such individuals, compared with the rate in control cases of 6% [13, 14]. 7  in 100 asthmatics have nasal polyps overall [15], but the rate depends on asthma subtype: amongst nonatopic asthmatics, nasal polyps occur 13% of the time; in atopic asthmatics, 5% of the time [16]. Whilst nasal polyps typically develop over a period of 9–13 years, in asthmainduced asthma, they form within 2 years [17]. In 10% of cases, asthma and nasal polyposis develop synchronously; the rest of the time polyp formation precedes asthma [18]. In females, nasal polyps increase the risk of asthma by

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1.6 times and the risk of hay fever 2.7 times [19]. Having CRSwNP worsens nasal symptoms in asthma. Olfactory impairment was shown by Alobid et  al. [20] to occur in CRSwNP as well as asthma (especially chronic asthma) and these olfactory alterations can be used to gauge the severity of both conditions. CRSwNP is found in between 36 and 96% of cases of aspirin hypersensitivity [16, 21–26], and radiological evidence of abnormality within the paranasal sinuses is present in approaching 96% of cases [27]. Cases where aspirin hypersensitivity, asthma and nasal polyposis co-occur generally do not have atopy. Their prevalence increases after the age of 40. The offspring of individuals with this triad also have higher rates of nasal polyposis and rhinosinusitis than the offspring of unaffected individuals [28]. HLA A1-B8 is found with higher frequency amongst individuals affected by asthma and aspirin hypersensitivity [29], whilst Klossek and colleagues found no sex bias in a group of 10,033 patients. Zhang et al. report the presence of immunoglobulin E-type antibodies to enterotoxins in most patients with aspirin hypersensitivity [30]. CRSwNP may have an association in immunologically uncompromised patients with both asthma and hypersensitivity to aspirin and other NSAIDs with an affinity for COX-1 (NSAIDCOX1). Reactions take place 1–4 h after ingestion of an NSAID acting on cyclooxygenase-1, resulting in symptoms of nasal inflammation, irritation to the conjunctivae or asthma. The co-occurrence of CRSwNP, NSAIDCOX1 hypersensitivity and asthma goes by several names: “Triad asthma”, “Samter syndrome”, etc., but usually now called NERD (NSAID-Exacerbated Respiratory Disease). For cases of CRSwNP there is a 30–40% occurrence of breathing difficulty and wheeze, and around 15% of cases have NERD itself [4, 5, 31, 32].

43.2 Pathophysiology The majority of scientific hypotheses to account for nasal polyps consider them to be the endpoint of a persistent inflammatory process resulting in stromal oedema and having an infiltrate of several different cellular kinds. It would be expected, consequently, that any form of persistent intranasal inflammation would lead to nasal polyposis [33]. However, the fact that this is not the invariable result is puzzling. Indeed, whilst certain aspects of the pathophysiology are known, the initial event is unknown, and may differ between cases. It is being increasingly accepted that the chronic inflammatory process underlying CRS is a result of abnormal interactions between the host and environment, dependent upon both intrinsic host factors and extrinsic elements affecting the mucosa of the nose and sinuses.

F. Boztepe et al.

43.2.1 Extrinsic Factors and Pathogen-Driven Hypotheses Taking the characterisation of CRS as a disorder involving inflammation and with abnormal interactions between host and environment as a starting point, the environmental factors have been researched over the last few years, but without clarity emerging on the role environmental factors play. It has not been demonstrated that working environments have any influence on CRSwNP rates [34]. One study concluded that smoking was less common in individuals with CRSwNP than in normal individuals (15% smoked, compared to 35% general population smoking prevalence) [34], a finding that has not been replicated elsewhere [13]. A single study associated wood burning stoves for heating with nasal polyposis [35]. There was an intensive research effort for many years focused on allergens as putative cause, based on the assumption that allergic hypersensitivities could predispose to nasal polyposis, a hypothesis suggested by the clinical and histopathological similarities between the conditions (watery nasal discharge, oedematous mucosae and abundant eosinophilic infiltrates). Epidemiological considerations also promoted this view, the “allergy theory” associating allergy occurrence with nasal polyp formation. Kern witnessed a rate of nasal polyposis of 25.6% in atopic individuals as against 3.9% in a control group [36]. The rate of allergy linked to an inhaled allergen in nasal polyp cases has been reported variously as 10% [37], 54% [38], or 64% [39]. However, other studies have not confirmed these findings, and show no significant association between atopy and NP [16, 39–42]. Larger scale epidemiological studies give little indication of support for the association, which was based on small numbers of cases where skin prick tests had been positive [15]. Some studies actually show that nasal polyps are no more frequent in allergy sufferers than in general [43]. Research using a questionnaire methodology has unearthed raised levels of food allergy in NP sufferers compared to healthy controls: 22% [13] and 31% [34]. Pang et  al. write that intradermal food tests were positive in 81% of NP sufferers in contrast to only 11% in a small sample of controls [9], but this result must be interpreted in the light of the knowledge that intradermal food allergy testing lacks reliability. Thus, how atopy relates to NP is unknown, even though epidemiological data may point to such an association, potentially the result of hypersensitivity developing secondarily at some point in the polyps’ growth. A number of researchers have recently posited allergy as a so-called “disease amplifier”, which can worsen the inflammatory response in NP individuals. In conclusion, our recommendation is for further investigation to resolve the relationship between hypersensitivity, CRS and NP.

43  Pathophysiology of Chronic Rhinosinusitis with Nasal Polyps

The emphasis on environmental factors in the inflammatory process of CRS had meant a move away from explanations based upon a pathogen, the “pathogen-driven hypotheses”, which we now discuss. The “fungal hypothesis” was the first theory that tried to link the aetiology of CRS with a pathogen. This theory drew support from the fact that CRSwNP patients produce abnormal immunological responses to fungal antigens found within the environment, e.g. Alternaria spp. The theory proposed that allergens from fungi became trapped by nasal secretions after being inhaled, and provoked an extreme T-cell response via antigen-presenting cells, leading to the chronic, eosinophilic inflammatory response. Supporters of the theory claimed that Altenaria possessed a protease, by means of which eosinophils were activated and underwent degranulation within the lumen. Despite an initial acceptance of this theory, doubts were cast on the role of fungi in pathogenesis by the failure of amphotericin treatment, whether topically or systemically, of affected individuals. Thus, whilst the majority of researchers now disagree that fungi are the ultimate aetiological agent, a proportion of researchers still considers that fungi may exacerbate or modify an already existent pathological process, at least in a subset of cases. The sole instance in which fungi have been definitively linked to pathogenesis of NP is in “allergic fungal sinusitis”, diagnosis of which depends on positivity of radioallergosorbent testing for fungal allergens, nasal polyposis, hyperdense areas in the sinuses as seen on CT, mucosal biopsy showing predominantly eosinophilic infiltration and presence of fungi within the mucous secretions of the sinus [44, 45]. The pathophysiological mechanism is a Type III hypersensitivity response that results in recurrent oedema of the mucosa, the antigen being re-presented and polyposis ensuing [46]. A potential bacterial aetiology has been the subject of extensive research, but neither the microbiological aspects nor the clinical importance of findings for CRSwNP have been resolved. To an extent, disagreement has arisen due to the different sampling techniques and methodologies employed by various studies [47, 48]. Implicated bacteria (which may act synergistically) in CRSwNP include: Staphylococcus aureus, Streptococcus pneumoniae, viridans streptococci (e.g. S. mutans), Moraxella catarrhalis and Haemophilus spp. [47–58]. Whilst coagulase-negative Staphylococci are often found in individuals with CRSwNP, they are also found in healthy individuals, thus rendering their significance unclear [48–52, 54, 59]. On the other hand, enteric rod-like bacteria which are Gram negative, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Escherichia coli and Enterobacteriaceae, are seldom seen in healthy controls, but have been found in CRS individuals [47, 49–51, 54, 60]. This group of organisms may be infective or merely colonising, but which remains

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obscure. CRS sufferers often have methicillin-resistant S. aureus (MRSA), which promotes antimicrobial resistance, but which alone does not appear to cause morbidity. The increasing existence of MRSA organisms in these individuals should prompt measures intended to reduce treatment resistance rates for diseases of the nose and sinuses, such as using bacterial culture to guide antibiotic prescribing [61]. Bhattacharyya and Kepnes, using an analysis based on isolating 701 colonies from 392 individuals with CRS [62], found that resistance to erythromycin is growing more quickly than for the following alternative agents: methicillin, clindamycin, gentamicin, tetracycline, sulphamethoxazole and levofloxacin. There has been considerable interest within recent times in the role of Staphylococcus aureus as a causative agent. One theory, dubbed the “staphylococcal superantigen thesis”, emphasises the occurrence of localised areas of hypersensitivity reaction to the growth of colonies of S. aureus, resulting in enterotoxin-specific IgE secretion [63–65]. Enterotoxin-specific IgE is extractable from mucosal tissues of individuals with CRSwNP, albeit in the absence of detectable circulating IgE of this type. Interestingly, CRS individuals not prone to nasal polyposis do not have such IgE [63]. Research has demonstrated no association between positivity of cutaneous prick testing and IgE levels, either specific or non-specific for enterotoxin, nor with other histologically determined allergy markers. There is, however, an association with eosinophil levels [66]. Why superantigen plays a role in only approximately 50% of CRSwNP cases is mysterious. Many researchers conclude from this that superantigen modifies rather than causes the disease. Finally, some researchers have explored the “biofilms hypothesis”. A number of different bacterial pathogens form a biofilm over polyps, allowing colonisation. The rate at which biofilm formation is found in CRS is between 28.6 and 100% [67–74], but apparent disparity in reported numbers may relate to methodological differences in biofilm identification. Whilst not an initiating event in the disorder, the presence of biofilms substantially increases the inflammatory response and alters how the patient responds to treatment. The existence of a biofilm corresponds to a more severe disease phenotype and leads to a poorer outcome postsurgically [75, 76]. This explains why biofilms are viewed as significantly modifying disease outcome.

43.2.2 Intrinsic Factors and the Theory of Host Susceptibility An intrinsic factor capturing much interest is the mucociliary clearance system. As appears in the section concerning anatomy and physiology of the sinuses, the cilia play a vital role in draining the sinuses and preventing persistent infections.

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Cases of CRS exhibit dysfunctional cilia, a dysfunction that is secondary and potentially can be reversed, given enough time [77]. One might predict CRS and recurrent infections of the respiratory tract would be frequent in patients whose ciliary function is already abnormal, such as cases of Kartagener’s syndrome or primary ciliary dyskinesia, and this indeed proves to be the case. Cases of Young’s syndrome typically have CRS, nasal polyp formation and azoospermia. Sufferers from cystic fibrosis (CF) have abnormalities within a cyclic adenosine monophosphate (cAMP)-dependent transmembrane chloride transportation protein, resulting in aberrant chloride transportation through apical membranes of epithelia. Nasal polyps formed in CF may be linked to this abnormality [33], whereby an excessively viscous mucus is produced that cilia are unable to shift, resulting in dysfunction of the cilia and eventual CRS. The formation of nasal polyps in CRS occurs in around 40% of such cases [78], the polyp being usually infiltrated with more neutrophils than eosinophils [1]. Biochemical defects in the eicosanoid pathway, which are strongly implicated in NSAID hypersensitivity, have been suggested as aetiological in CRSwNP cases [79, 80]. The imbalance between the pro-inflammatory leukotrienes and the protective PGE2 (prostaglandin), whereby inflammation predominates, has been invoked to explain polyposis of both NSAID-sensitive and NSAID-insensitive forms of CRSwNP.  Although this explanation has much theoretical plausibility, it lacks clinical confirmation, since leukotriene antagonists are of limited efficacy in CRSwNP. Immunodeficiency has also been considered as a potential precursor to CRS. Congenital immunodeficiency syndromes become apparent early in life, but acquired immunodeficiency can happen at a later stage and be revealed by CRS. Chee et al. examined cases of treatment resistance in sinusitis using a retrospective methodology. They identified an unanticipated elevated rate of immunological dysfunction in these cases [81]. Sixty patients had in vitro evaluation of T-cell functioning, of which 55% had T cells which underwent abnormal expansion in numbers when represented with previously encountered antigens. These patients also had abnormal levels of various immunoglobulins: immunoglobulin levels in general were encountered in 18% of cases; IgA was low in 17%; and 5% had low levels of IgM.  Ten percent had diagnosable common variable immunodeficiency, and 6% selective IgA deficiency. These findings highlight the need for routine testing of immunological function in all cases of CRS. A more contemporary hypothesis to explain the aetiology of CRS is the immune barrier hypothesis. This theory posits CRS as the result of a defective mechanical barrier plus or minus innate immunological responses within the mucosa of the sinuses and nose. According to the theory, mechanical defects allow overgrowth of multiple bacterial species,

F. Boztepe et al.

which further damage the mechanical barrier and provoke an adaptive immune reaction [82]. Locally defective STAT3 pathways are seen in certain cases of CRS and may be how the pathogenesis develops [83]. Systemically, defects in STAT3 are seen in autosomal dominant hyper-IgE syndrome, which resembles CRSwNP in many details [84]. Whilst CRSsNP features elevated IFN levels in the nose and sinuses, indicative of an inflammatory response led by T-helper 1 cells [85–87], nasal polyps consistently show elevated eosinophil levels and the secretion of eosinophil-­ derived molecules, pointing instead towards a T-helper 2 (Th2)-led process in CRSwNP [66, 86, 88, 89]. The classical immune barrier theory does not account for why there is a bias in favour of Th2 responses within many phenotypes of CRS, including the combination of Th2- and B-cell infiltrates seen in occidental cases of CRSwNP.  This may be taken as evidence of other defects or mechanisms awaiting discovery before the theory can explain why an inappropriate response of the adaptive immune system occurs confined to one locality. Genes thought to predispose towards Th2 domination include: TSLP, IL-33 and IL-25. Genes that mediate B-cell involvement are: BAFF, CXCL12 and CXCL13 (100– 102). Dysfunction of T-regulatory cells (Tregs) can also be invoked to explain Th2 predominance. Mounting evidence points to the role of Tregs in suppressing allergic and autoimmune responses [90, 91]. Tregs prevent T cells differentiating into T-helper 17 cells and maintain the balance between Th1 and Th2 responses [91, 93]. Tregs usually express the FOXP3 transcription factor protein (Forkhead box 3) [92], a protein with reduced levels in CRSwNP individuals, both Chinese and European [85, 88, 94]. If the Th2 response is either excessive or inappropriate, existing mechanical barrier defects may be worsened and innate immune capacities diminished, resulting in a spiralling disease process. In cases of CRSwNP at maximum severity, local autoantibodies have been observed, which add to preexisting damage [95].

43.2.3 Hypotheses Involving Remodelling of the Sinonasal Mucosae Opinion is divided as to whether polyps are normal mucosa that has been evaginated and the stroma of which subsequently becomes oedematous, or are distinct from normal mucosa. Bernstein reviewed the existing literature on polyps, and, putting his own findings from bioelectric studies of polyps together with Tos’s research, came up with a persuasive theory of polyp formation [96, 97]. According to Bernstein, inflammatory adaptations arise in the nasal wall laterally or within the sinuses, triggered either by immune encounters with bacteria or viruses, or through turbulence in the airflow. Polyps most often develop in areas of turbulent airflow, such as where mucosal surfaces come into contact with each other, e.g. the

43  Pathophysiology of Chronic Rhinosinusitis with Nasal Polyps

anterior portion of the ethmoid area, even more so when the mucosa is already inflamed. The submucosa may become ulcerated or may prolapse, following which there is regrowth of the ulcerated mucosa, and new glands form. Whilst all this is going on, polyps may start to form, due to increased sodium uptake and thereby increased retention of water. The sodium uptake occurs because sodium channels on the luminal surface of respiratory epithelia are compromised by the ongoing inflammatory response of the epithelium itself, the vascular endothelium and the fibroblasts in the stroma [33]. Other theories emphasise vasomotor factors or posit interruptions to epithelial continuity. According to vasomotor theorists, an imbalance results in the vessels becoming over-­ permeable and loss of vasomotor regulation. As a result, mast cells degranulate, releasing, for example, histamine. Chronic persistence of these substances leads to oedema which is worsened by the impaired venous drainage. The area forming the root of the polyp is particularly affected. Support for this hypothesis comes from noting the relatively acellular nature of the polyp stroma and the absence of new vessels or neurovascular regulation [33]. Theories based on the epithelium rupturing as an initiating event in polyp formation, suppose that the turgidity of the mucosal surface is increased by pre-existing conditions such as atopy or infection. When rupture occurs, the lamina propria prolapses, resulting in formation of a polyp. Gravity may play a role in enlarging the lesion, as may blockage to the venous drainage. Despite superficial similarities to Bernstein’s thesis, overall it is less persuasive than the bioelectric hypothesis. In any case, neither theory adequately accounts for how the process is triggered, nor why inflammatory subtypes of CRSwNP exist [33].

43.3 Conclusions Despite the existence of competing theories to explain how nasal polyps arise, no single theory can explain all aspects of nasal polyposis. There is agreement that host and environment somehow interact in a dysfunctional fashion within the nasal cavity or the sinuses. For inflammatory conditions involving mucosae, there is a general consensus that all involve an interplay between host factors (intrinsic elements), commensal organisms, possible pathogens and external stresses. Whilst this interplay links all such disorders, wherever they occur, the exact details and relative weighting of the various elements is the subject of ongoing investigation. Cultural and ethnic differences may affect how susceptible individuals are and what pattern of disease subsequently develops. Between individuals, the pattern of exposure that occurs may be termed the “exposome” (à la genome, metabolosome, etc.). Culture and geography doubtlessly play a significant role in the components making up the overall exposure.

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Future research, it seems, needs to concentrate on subtyping the different CRSwNP phenotypes by predominant inflammatory pattern, linking these types with improved modalities of treatment. How remodelling occurs is also a vital question to be addressed. Where prevention is possible, this too is of the utmost importance.

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Medical Treatment of Nasal Polyposis

44

İhsan Kuzucu, İsmail Güler, and Nuray Bayar Muluk

44.1 Introduction Nasal polyps cause nasal blockage, runny nose, and decrease in or loss of olfaction, but their etiology is actually not known. The treatment of chronic rhinosinusitis (CRS) with nasal polyposis is directed at dealing with these symptoms, and consists of both surgical and medical remedies; nevertheless there is no treatment protocol that is universally recognized [1]. The treatment of nasal polyps depends on the etiologic elements. However, in the majority of cases, this is not clear. Even when the patient has allergic background, no clinical proof demonstrates that the treatment of these allergies could minimize or eradicate polyps. Since the main etiology in the majority of cases is inflammation, medical treatment consists of nonspecific therapies for this inflammation related problem [2]. In this chapter, alternatives of medical treatment for nasal polyposis are described.

44.2 Topical Corticosteroids Nasal corticosteroid sprays may diminish or slow down the development of small nasal polyps; nevertheless, they are rather not effective in massive nasal polyposis. Intranasal steroids are most beneficial in the postoperative interval to protect against or slow down regrowth of the polyps [2]. When a polyp has been identified, the patient is given an intranasal corticosteroid preparation. Betamethasone sodium phosphate drops applied in the “head down and forward” position is the most effective start [3]. If an individual is unable

İ. Kuzucu (*) · İ. Güler Department of Otorhinolaryngology, University of Health Sciences, Ankara Numune Training and Research Hospital, Ankara, Turkey N. Bayar Muluk Department of Otorhinolaryngology, Medical Faculty, Kırıkkale University, Kırıkkale, Turkey

to consider this position, the preparation can be applied by another person, with the individual lying supine with the head extended over the edge of the bed. Providing the drops in the “head down and forward” position may create a dramatic shrinking of the polypoid tissues in the next 48 h. After an obvious diminishment in the dimensions of the polyps has been attained, prolonged maintenance of this diminishment may be accomplished by continual using of intranasal topical steroid sprays such as fluticasone propionate, budesonide, or beclomethasone dipropionate [4, 5]. Individuals can be convinced concerning the long term safety of these medicines, regarding their local and systemic effects [6]. Rudmik et al. published a meta-analysis about the effects of intranasal steroids (low-dose administration) on symptoms in individuals with nasal polyps. The analysis suggested that intranasal steroids help with nasal symptoms in patients with CRS and nasal polyposis. The study failed to specify the influence of nasal steroids on polyp size or regression, but instead focused simply on improvement of symptoms. One should realize that the studies included in the metaanalysis did not determine polyp size; no comment could be made regarding the underlying mechanisms of improvement, since they may be due to improvement in associated rhinitis, instead of an effect on the nasal polyposis [7]. Tos et  al. [8] likewise demonstrated that nasal powder (140 mcg) and spray (128 mcg) of budesonide were significantly more efficient compared to control regarding shrinkage of polyps, recovery of olfaction, decrease in symptom score, and overall evaluation in comparison with placebo. Keith et  al. [9] designed a randomized, parallel-group, placebo-controlled, multicenter trial with 52 individuals in both groups, in which the effects of intranasal fluticasone propionate drops of 400 μg given daily for 12 weeks were compared to placebo. No significant shrinkage of polyps was seen yet nasal obstruction and peak nasal inspiratory flow (PNIF) were improved significantly in fluticasone administered individuals. A couple of more patients with epistaxis in the fluticasone group were noticed. No unwanted effects were documented [10].

© Springer Nature Switzerland AG 2020 C. Cingi, N. Bayar Muluk (eds.), All Around the Nose, https://doi.org/10.1007/978-3-030-21217-9_44

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44.3 Systemic Corticosteroids Oral steroids are one of the mainstays for the medical treatment of nasal polyposis. In adults, the majority of clinicians start using prednisone (30–60  mg) for 4–7  days and taper drugs over 1–3  weeks. Dose may differ for children; nevertheless the maximum dosage is generally 1  mg/kg/day for 5–7  days, subsequently lowering the dose in 1–3 weeks. Response to steroids seems to be determined by the presence or absence of eosinophilia; therefore, individuals having polyps and allergic rhinitis or asthma have a greater chance of healing in response to this remedy [11]. Individuals whose polyps improve with oral steroids can be retreated safely 3–4 times a year, particularly when surgery is not considered. The mechanism of action of steroids is not clear. An in vitro study demonstrated that corticosteroids could induce apoptosis in the inflammatory human cells within nasal polyps [12–14]. A far more remarkable option to handle polyps medically is to offer oral corticosteroids like dexamethasone or prednisolone. Dexamethasone for 9  days (12  mg/3  days, 8  mg/3  days, 4  mg/3  days) is generally effective in creating a remarkable diminishment in the dimensions and symptoms of nasal polyposis. This regime is contraindicated, nonetheless, in patients with diabetes mellitus, severe hypertension, advanced osteoporosis, herpetic keratitis, or gastric ulceration. The generation of endogenous cortisol may be raised with synthetic adrenocorticotrophic hormone which is Synacthen Depot, given twice intramuscularly as 1  mg injections which are 2  days apart (with the individual observed for a minimum of 1  h after each injection). Corticotrophin and high dose oral steroids are most valuable whenever a fast improvement is necessary, and this sort of treatment can be provided 3–4 times a year in the majority of individuals [6]. A report by Moss et al. pointed out that although visual issues may appear after steroid injections for nasal polyps, the probability is low. The research included 78 individuals with chronic rhinitis or sinusitis who were given a total of 237 injections of triamcinolone acetonide. The injections were either intraturbinate (152 injections) or intrapolyp (85 injections). One individual experienced a visual alteration right after an intrapolyp injection; however it was temporary and disappeared spontaneously. The researchers carried out an assessment of nine case series associated with a total of 117,669 intranasal steroid shots as well, of which simply three (0.003%) brought about visual complications; every one of these all disappeared spontaneously without permanent visual damage [15].

44.4 Short-Term Treatment with Antibiotics In a study by van Zele et  al. the effect of doxycycline (100 mg/day after the first day of 200 mg) for 20 days with methylprednisolone administered for 3  weeks (32  mg for 1 week, 16 mg for 1 week, and finally 8 mg for 1 week) was compared with placebo. Similarly, Schalek et  al. [16] carried out another placebo-controlled study with 23 S. aureus enterotoxin-producing strain-positive patients, undergoing FESS who were randomized to oral anti-staphylococcal antibiotics (co-trimoxazole, amoxicillin/clavulanate, or quinolone) for 3 weeks, or placebo. Groups were compared to each other preoperatively, at 3 and 6 months postoperatively with endoscopic scores and SNOT-22 questionnaire. Fairly superior scores were achieved with antibiotics; however, the difference was not significant. Inflammatory markers were assessed in blood and nasal secretions, polyp dimensions were determined, and symptoms were recorded. Methylprednisolone displayed a brief yet remarkable impact upon polyp dimensions and symptom scores. Doxycycline showed a considerable yet small impact on polyp dimensions in comparison to placebo that existed through the time span of the study for 12 weeks [16, 17].

44.5 Long-Term Treatment with Antibiotics In an uncontrolled trial 20 individuals having CRS with nasal polyposis were given clarithromycin 400 mg/day for a minimum of three months. In the group whose polyps were diminished in size, the IL-8 levels which were significantly higher before macrolide treatment decreased compared to those who had no change in the size of their polyps [18]. In a different uncontrolled trial, 40 individuals overall were given either roxithromycin 150 mg alone or combined with an antihistamine (azelastine) for a minimum of 8  weeks. Small polyps reduced in size more likely and this occurred in approximately 50% of the sufferers [19]. A small open study, with twelve patients given roxithromycin 150 mg once a day, demonstrated a decrease in IL-8 and increased aeration on CT as well [20].

44.6 Anti-IgE Levels of total IgE in blood serum, nasal secretions, and nasal polyp homogenisates were increased in individuals having CRS and nasal polyposis compared to control group. Omalizumab® is a recombinant DNA-derived human-

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ized IgG1k monoclonal antibody that selectively binds to human IgE, and decreases levels of tissue and serum IgE. Omalizumab® is approved for individuals with moderate-to-severe or severe allergic asthma. Two anecdotal studies [21, 22], a pilot trial in eight patients [23], and a case series [24] demonstrated favorable effects of this drug in patients with CRS and nasal polyposis. Pinto and co-workers carried out a placebo-controlled, double-blind, randomized trial of Omalizumab® in 14 severe CRS patients (12 with nasal polyps) refractory to standard remedies in addition to surgery. Patients having serum levels of total IgE between 30 and 700  IU/mL before treatment were included in the study. All patients were given 0.016 mg/kg of anti-IgE per IU total serum IgE/mL subcutaneously or placebo injections every 4 weeks for 6 months in addition to other medication. Comparison of pre- and posttreatment sinus opacification in coronal CT scans was primary outcome parameter. The median change of sinus opacification in individuals receiving anti-IgE treatment compared to placebo treated patients was 11.9% vs. 5.9% (p  0.2) [34].

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In a controlled, open-label study, 64 patients having CRS with nasal polyps were given intranasal furosemide spray that was administered 200 μg daily subsequent to sinus surgery. Forty patients in the control group did not receive any treatment. Upon 6 years, 4 patients in the furosemide group and 12 patients in the control group had recurrent polyposis (p