Pharyngeal Dysphagia Secondary to Brain Injury

OTOLARYNGOLOGY RESEARCH ADVANCES SERIES

HANDBOOK OF PHARYNGEAL DISEASES: ETIOLOGY, DIAGNOSIS AND TREATMENT

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Handbook of Pulmonary Diseases: Etiology, Diagnosis and Treatment Krisztián Fodor and Antal Tóth (Editors) 2009. ISBN: 978-1-60741-898-6

Snoring: Causes, Diagnosis and Treatment Eugene Lefebvre and Renaud Moreau (Editors) 2010. ISBN: 978-1-60876-215-6

Handbook of Pharyngeal Diseases: Etiology, Diagnosis and Treatment Aaron P. Nazario and Julien K. Vermeulen (Editors) 2010. ISBN: 978-1-60876-430-3

OTOLARYNGOLOGY RESEARCH ADVANCES SERIES

HANDBOOK OF PHARYNGEAL DISEASES: ETIOLOGY, DIAGNOSIS AND TREATMENT

AARON P. NAZARIO AND JULIEN K. VERMEULEN EDITORS

Nova Science Publishers, Inc. New York

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Library of Congress Cataloging-in-Publication Data Handbook of pharyngeal diseases : etiology, diagnosis, and treatment / editors, Aaron P. Nazario and Julien K. Vermeulen. p. ; cm. Includes bibliographical references and index. ISBN 978-1-61761-179-7 (E-Book) 1. Pharynx--Diseases--Handbooks, manuals, etc. I. Nazario, Aaron P. II. Vermeulen, Julien K., 1965- [DNLM: 1. Pharyngeal Diseases. WV 400 H236 2009] RF481.H36 2009 616.3'2--dc22 2009035679

Published by Nova Science Publishers, Inc.  New York

Contents

Preface vii Chapter I Neurological Diseases with Pharyngeal Dysfunction 1 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini Chapter II Pharyngeal Dysphagia 49 P. Claire Langdon and Kim M. Brookes Chapter III Effects of Maxillofacial Disorders on Pharyngeal Structures and Orthodontic Treatment Modalities 79 Nihat KILIÇ and Husamettin OKTAY Chapter IV Velopharyngeal Dysfunction 109 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour Chapter V Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 137 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu Chapter VI Management of Swallowing Difficulty in Pharyngeal Diseases 169 Byung-Mo Oh and Nam-Jong Paik Chapter VII Infections of the Pharynx 193 Mustafa Gul Chapter VIII Malignant Nasopharyngeal Tumors in Children 213 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre, Natacha Teissier, Paul Freneaux and Daniel Orbach Chapter IX Harmonic Scalpel® in the Treatment of Snoring 235 A. Salami, R. Mora, M. Bavazzano, L. Guastini, B. Crippa and M. Dellepiane

vi Contents

Chapter X Retropharyngeal Hematoma 249 Tun-Yen Hsu Chapter XI Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy and Manometry (Videfluoromanometry) 263 S. Cappabianca , L. Brunese, A. Reginelli, M.G. Pezzullo, G. Gatta, R Grassi and A. Rotondo Chapter XII Treatment of Cervical Fistulae after Microsurgical Reconstruction Following Radical Ablation of Head and Neck Cancers 279 Masaki Fujioka Chapter XIII Pharyngeal Dysphagia Secondary to Brain Injury (Stroke and Traumatic): Analysis of Tracheal Aspiration 299 Rosa Terre Chapter XIV Nasopharyngeal Carcinomas: What Radionuclide Imaging Can Do? 311 Ambreen Khawar Chapter XV Reconstructive Options for Free Radial Forearm Flap Donor Defect in Pharyngeal and Laryngeal Reconstruction 323 Kao-Ping Chang and Chung-Sheng Lai Chapter XVI Distribution of Tumor Necrosis Factor Producing Cells in Chronic Tonsillitis 331 Milan Stankovic, Miroljub Todorovic, Verica Avramovic, Misa Vlahovic and Dragan Mihailovic Chapter XVII Peritonsillar Abscess 341 Olaf Zagólski Chapter XVIII Malnutrition and Inflammation-Induced Abnormal Serum Trace Element Concentration in the Patients with Pharyngeal Diseases Who Has Received Enough Trace Elements Intake by Enteral Nutrition 347 Hitoshi Obara, Yasuka Tomite and Mamoru Doi Chapter XIX Isolated Uvulitis and the Cannabis Connection 357 Andrew Gunn Index 363

Preface

Pharyngeal disease and/or dysfunction is responsible for many cases of dysphagia (difficulty swallowing). This can result in dehydration, malnutrition and life-threatening conditions such as aspiration pneumonia and choking. This book discusses the causes of and current treatment approaches in managing and alleviating pharyngeal dysphagia. Also evaluated are the effects of the developmental disturbances in the maxillofacial region on the pharyngeal and neighboring structures. Furthermore, the effects of orthodontic and/or orthopedic approaches are assessed, such as maxillary protraction, rapid maxillary expansion, and activator. The videofluoroscopic swallowing study is also introduced as a standard method for the diagnosis of pharyngeal diseases and to describe the basic principles and approaches of the treatment of pharyngeal dysphagia. In addition to pharyngeal dysphagia, the diagnostic and therapeutic approach to childhood malignant nasopharyngeal tumors are reviewed. The authors also review the known prognostic factors of these diseases in order to discuss treatment adaptation, especially in young children. Other chapters in this book explore the cardinal manifestation of the neurological diseases, a discussion of the improved imaging systems and new radioactive agents in diagnosing and treating various tumors, a review of the potential causes of isolated uvulitis, retropharyngeal hematoma, and adenotonsillar disease and the treatment for peritonsillar abscess, a complication of acute bacterial tonsillitis, and other pharyngeal diseases. Chapter I - Neurological diseases can affect the pharynx in many different ways, including its motility and somatic sensation. Therefore, these diseases can impair the main pharyngeal functions, causing disorders of swallowing, speech and breathing. The premise of this chapter is to provide dependable and meaningful knowledge as the foundation for clinical work. This chapter is divided into five subsections based on the cardinal manifestation of the neurological diseases. Each subsection contains disciplined presentation of scientific data and lucid description of etiology, pathophysiology, diagnosis and treatment. The first subsection includes disorders of motility, such as motor paralysis and movement disorders. The second subsection comprises disorders of somatic sensation: for instance, pharyngeal anesthesia and neuropathic pain. The third subsection consists of disorders of swallowing, describing the underlying neural mechanisms of dysphagia and aspiration, and their management. The fourth subsection is focused on the disorders of the articulation of speech: dysarthria and anarthria. The fifth subsection emphasizes breathing viii Aaron P. Nazario and Julien K. Vermeulen disorders, such as obstructive sleep apnea of neurological origin. It is important to consider that patients with neurological diseases and pharyngeal dysfunction consult many physicians from different specialties and other professional caregivers because of a multitude of problematic symptoms. In the quest to offer the best assistance, the reader is encouraged to invade those obscure and difficult territories in the domain of neurologists and expand his notion of a disease by knowledge of its current scientific foundations. The comprehensive involvement of two neurologists in writing this chapter has promoted a uniform approach across subject matter that should be pleasing to the reader. Chapter II - Pharyngeal disease and/or dysfunction is responsible for many cases of dysphagia (difficulty swallowing). This can result in dehydration, malnutrition and life- threatening conditions such as aspiration pneumonia and choking. There can be a significant social cost in dysphagia, with patients who experience impairment in their ability to eat normally becoming isolated or embarrassed. Eating and swallowing problems can arise from a number of different aetiologies. These include neurological causes such as brainstem and cortical stroke, cranial nerve dysfunction, neoplasms including brain tumours and head and neck cancers, surgery, head injuries, congenital defects, myopathies, progressive neurological diseases such as Parkinson's Disease and Motor Neuron Disease (Lou Gehrig's Disease), trauma and burns. Dysphagia and its management is a highly specialised area which incorporates the skills of a multidisciplinary team in diagnosis and treatment. In recent years, the research into pharyngeal dysphagia has expanded knowledge of the area and has provided new and effective ways in which to alleviate eating and swallowing impairment. This chapter discusses causes of and current treatment approaches in managing and alleviating pharyngeal dysphagia. Chapter III - The human body constitutes a functional entity, no part of which can be varied without entailing some changes in other parts. Similarly, the facial skeleton and the dentition are functional parts of the skull as a whole. The stomatognathic system consists of mouth, upper and lower jaws, teeth, upper respiratory tract, pharynx, and the other structures related with mastication, deglutition, respiration, speech, and the functions in a functional entity according to functional matrix theory. Developmental disorders in any organ of this system and/or functional aberrations will also affect the other components. The relationships between respiratory disturbances and maxillofacial growth and development have been the center of interest among orthodontists for years. Animal and human studies have demonstrated that a close relationship exist between nasal respiration and dentofacial form and development. Mouth-breathing causes serious negative effects on the normal development of nasomaxillary and craniofacial structures. Maxillofacial abnormalities are related with the nasal and pharyngeal problems including impaired nasal respiration, mouth breathing, pharyngeal infections, breathing disturbances and even conductive hearing loss. This chapter aimed to evaluate the effects of the developmental disturbances in maxillofacial region on the pharyngeal and neighboring structures. The present paper will also assess the effects of orthodontic and/or orthopedic approaches such as maxillary protraction, rapid maxillary expansion, activator, headgear, and etc. Chapter IV - The velopharyngeal port is the area bounded by the soft palate, the posterior pharyngeal wall and the lateral pharyngeal walls. Insufficient closure of this port will lead to Preface ix leakage of air during speech (with the acoustic consequence of hypernasality) and leakage of fluids during swallowing (nasal regurgitation); a problem that is called velopharyngeal dysfunction (VPD). Its causes may be congenital or acquired. Overt cleft palate - even after its repair - is the commonest cause. Submucous cleft palate, neuromuscular disorders of the palate, palatal fistula are other causes. Post-operative VPD may occur following adenoidectomy, palatopharyngoplasty for sleep apnea and maxillary advancement. However, the cause may sometimes be unknown. Management of this problem is rather complex and requires a teamwork approach. Members of the team share in primary evaluation, planning of treatment and following up the results of intervention. At least, an otolaryngologist, a phoniatrician/speech language pathologist, and prosthetist should work together during management. Treatment decisions must be based, not only on subjective practitioner‘s impression, but also on data provided by some clinical diagnostic tools, such as nasopharyngoscopy, and videofluoroscopy. The treatment approaches may be non-surgical in the form of speech therapy or prosthetics, and/or surgical in the form of palatal surgery (e.g. Z-plasty or intravelar veloplasty) or pharyngeal surgery (e.g. pharyngoplasty, pharyngeal flap or posterior pharyngeal wall augmentation). Chapter V -Waldayer‘s lymphatic ring represents an anatomo-physiological defense structure localized at the gate of both the digestive and respiratory system, with two major roles – reducing the amount of germs that can enter the body and a tampon role between the immune system and different antigens, ensuring a normal and correct differentiation of the B and T lymphocytes. The ring is composed of 6 more or less individualised anatomic structures – 2 palatine tonsils, 2 tubal tonsils, 1 pharyngeal tonsil (Luschka), and a tonsil at the base of the tongue – and a variable amount of disseminated interposed lymphoid follicles. All the lymphoid structures of Waldayer‘s ring have similar architecture. They are constituted from a covering epithelial tissue which sends infoldings to the underlying stroma, forming the crypts, surrounded by lymphoid follicles disposed in lobules, separated by lax connective tissue. The epithelium is keratinised – malpighian type excepting the pharyngeal tonsil who has a respiratory pseudo-stratified epithelium. The amigdalian crypts are deep and narrow in palatine and pharyngeal tonsils and superficial in lingual and tubal tonsils. This particular aspect makes the palatine and pharyngeal tonsils more susceptible to inflammations explained by stasis of the pathogens at the cryptic level. Amigdalian cryptic epithelium also named lymphoepithelium due to the increased number of lymphocytes contained into it plays a significant role in the immune response initiation at the amigdalian level as, the luminal antigens from the crypts are taken over and presented to some specialized cells localized at the level of the amigdalian epithelium. In some cases at the level of tonsils covering epithelium, relatively frequent erosions can be obsserved, leading to a direct contact of the amigdalian follicles to the saprophyte or pathogenic flora present in the pharynx. The erosions of the surface epithelium are the effect of aggressive pathogenic agents. Chapter VI - In order to prevent repetitive subglottic aspiration or suffocation, coordination of the pharyngeal movement is critical in the swallowing process. However, diverse diseases can cause difficulties in the neuromuscular coordination of the pharynx. Thorough attention to patients' history and careful investigation of the pathophysiology are important in treating the swallowing difficulty. Also, it is mandatory to precisely assess the patient's pathological state with the aid of videofluoroscopic swallowing studies, currently x Aaron P. Nazario and Julien K. Vermeulen accepted as the standard diagnostic test, and to prescribe adequate treatment based on the test results. Although the clinical trial-based evidence is not sufficient, a satisfactory functional outcome can be achieved in many patients through individually tailored rehabilitation strategies. The purpose of this chapter is to introduce the videofluoroscopic swallowing study, as a standard method for the diagnosis of pharyngeal diseases and to describe the basic principles and approaches of the treatment for pharyngeal dysphagia. Chapter VII - The pharynx is a common site of infection. The etiology is usually infectious, with 40-60% of cases being of viral origin and 5-40% of bacterial origin. A number of different viruses can infect the human throat. The most common viral causes of pharyngitis are adenovirus and Epstein-Barr virus however others include, influenza virus, herpes simplex virus, rhinovirus, coronavirus, respiratory syncytial virus and parainfluenza virus. The primary cause of bacterial pharyngitis is Streptococcus pyogenes, however others include, Corynebacterium diphtheriae, Arcanobacterium haemolyticum, Neisseria gonorrhoeae, Chlamydophila pneumoniae and Mycoplasma pneumoniae. Some cases of pharyngitis are caused by fungi such as Candida albicans. Infection of the pharynx is associated with pharyngeal pain. Inspection of the pharynx reveals that affected tissues are red and swollen. Depending on the causative microorganism, enlarged and tender nasopharyngeal lymph nodes, vesicles, inflammatory exudates, mucosal ulceration, headache and aching muscles and joints may be observed. The diagnosis of viral pharyngitis is made by examining the throat and serological tests. The gold standard for diagnosis of bacterial pharyngitis is culture on agar. The primary purpose of a throat culture is to isolate and identify organisms from the pharynx that cause infection. The specimen for pharynx culture is obtained by wiping the patient's throat with a cotton swab. Throat cultures should be taken before the patient is started any antibiotic medications. An accurate diagnosis is essential to prevent unnecessary use of antibiotics. Chapter VIII - Primary malignant nasopharyngeal tumors are relatively rare in children. The most frequent childhood neoplasms in this region are rhabdomyosarcoma (RMS), Undifferentiated Carcinoma of Nasopharyngeal Type (UCNT) and Non-Hodgkin‘s Lymphoma (NHL). Children with these tumors usually present with nasal obstruction, headache, nasal swelling or cervical node involvement. The nasopharyngeal mass may be discovered during an ear, nose and throat examination and is confirmed by medical imaging. The diagnosis may be suspected on fine needle aspiration and is confirmed by biopsy of the nasopharyngeal mass or cervical lymph node. The treatments and prognoses differ for these 3 types of tumors. The objective of this paper is to review the diagnostic and therapeutic approach to childhood malignant nasopharyngeal tumors such as RMS, NHL and UCNT. The authors also review the known prognostic factors of these diseases in order to discuss treatment adaptation, especially in young children. Chapter IX - Primary snoring is usually considered to be a consequence of soft palate vibration caused by a partial upper airway collapse during sleep. Uvulopalatopharyngoplasty (UPPP) is a surgical treatment used to remove tissue in the throat for snoring and/or sleep apnea syndrome. UPPP is still the most frequently used surgical treatment for snoring and/or sleep apnea syndrome. Innovative advances have recently introduced regarding instrumentation, energy sources, and devices aimed at Preface xi facilitating surgical procedures in terms of efficient hemostasis, tissue legation and dissection, as well as reduction in surgical time: although curative for many patients, these procedures present side effects. The Ultracision Harmonic Scalpel® is an ultrasonic cutting and coagulating surgical device. The equipment consists of a generator, an hand-piece, and specific inserts. The mechanism of the Harmonic Scalpel® (HS) is based on transforming electrical energy into mechanical movement of 55.5 kHz frequency. The high-frequency ultrasonic vibrations produced by the HS cause an effect referred to as cavitation whereby the collagen and proteoglycans in the tissue become denatured and then combine with the tissue fluids to form a coagulum. The pressure exerted on the tissue by the blade surface collapses blood vessels and allows the coagulum to form a hemostatic seal. The HS controls bleeding by coaptive coagulation at low temperatures, ranging from 50°C to 100°C. By contrast, electrosurgery and laser coagulate by burning (obliterative coagulation) at higher temperatures (150– 400°C). The vibration frequency of HS is optimal for soft tissue and does not cut mineralized tissue (lower frequency waves need to be utilized). In UPPP, among the available hand-pieces and inserts, a specific hand-piece and insert was preferred: the insert, shaped like scissor, had a sharp inner beveled radius for cutting under tension, a blunt outer radius for coaptive coagulation, and a flat side for surface coagulation. In all the patients treated, the HS allowed rapid and easy intraoperative management and a precise and safe cut, especially in difficult anatomic sites. The operating fields were blood free with perfect intraoperative visibility. These features facilitate the use of the HS in tight spaces, where precision is essential. Postoperatively, all patients had a recovery of snoring (no complications with regard to haemostasis or other major complication, were noted in our study group), with an acceptable level of pain. Chapter X - Retropharyngeal hematoma is an uncommon entity of disease of pharynx. A variety of causes are known including direct neck trauma, whiplash injury, foreign body ingestion, deep neck infection, metastatic carcinoma, anticoagulant drugs, coughing, sneezing, straining, or even spontaneous bleeding. Diagnosis can often be inferred from history but exploration may be required for confirmation. Due to pharyngeal wall swelling, it wound cause sore throat, dysphonia, dysphagia or even dyspnea while airway compromise. Physical examination may reveal stridor. In some severe cases, subcutaneous bruising over neck and anterior chest may be found. Narrowing of the pharynx can be detected simply by neck soft tissue lateral view X-ray or by endoscopic examination. Computed tomography (CT) scan or Magnetic Resonance Imaging (MRI) examination should also be necessary because the hematoma may involve inferiorly to the mediastinum causing anterior displacement of trachea or esophagus which complicate management strategy. Securing the airway is the most crucial. In traumatic cases, cervical spine immobilization is also important. Surgical evacuation of a retropharyngeal hematoma can be necessary when the hematoma is large, breathing inadequate or conservative management unsuccessful. Specific management against the possible specific cause should also be taken.

xii Aaron P. Nazario and Julien K. Vermeulen

Chapter XI – Swallowing is an essential biological function, and any alteration can determine severe consequences, such as malnutrition, dehydration, aspiration pneumonia or airway obstruction. Swallowing disorders have a variety of causes: neurological disease, neoplasia of the oral cavity, the pharynx and/or the larynx, connective tissue disease, trauma, infection or iatrogenic illness. Because dysphagia covers a wide range of symptoms, from a vague or subtle sensation of abnormal swallowing in an ambulatory alert patient, to a severely handicapped bedridden patient who does not seem to be able to swallow at all, a complete evaluation of the swallowing mechanism should be carried out Chapter XII – Background: Cervical fistulae caused by unsuccessful wound healing after microsurgical reconstruction are sometimes seen in patients who have undergone radical ablation of head and neck malignancies. They can cause long-term distress for the patient and decrease their quality of life. Furthermore, treatment of fistulae is challenging because these patients have often undergone radiotherapy. Methods: Records were reviewed of 83 patients with head and neck cancer who required radical resection and microsurgical reconstruction in our unit from 2004 through 2007. Among these patients, 11 developed cervical fistulae postoperatively. The associations between radiotherapy, chemotherapy, tumor size, lymph node metastasis, and type of flaps and the development of postoperative fistulae were observed. Results: All 11 patients who developed cervical fistulae had undergone radiotherapy, which was identified as the most important risk factor for postoperative cervical fistulae. All the fistulae were successfully treated with a pectoralis major musculocutaneous flap. Conclusions: Cervical fistulae that occurred after radiotherapy and microsurgical reconstruction do not heal spontaneously despite aggressive medical wound management. Skin grafts and local cutaneous flaps harvested from within the radiation field are unreliable and rarely provide adequate and stable coverage. Salvage surgery using a musculocutaneous flap is recommended to facilitate healing of these complex wound. Chapter XIII – Aims: To ascertain the videofluoroscopic (VFS) pharyngeal alterations in patients with tracheal aspiration, secondary to brain injury (stroke and traumatic brain injury - TBI-) and its evolution. Methods: Forty six patients (twenty patients with stroke and twenty-six patients with severe TBI) with videofluoroscopic diagnosis of tracheal aspiration were prospectively evaluated. Videofluoroscopic examination were performed at admission and repeated at 1, 3, 6 and 12 months of follow-up. Results: In stroke patients at admission, there were 70% of patients with mean pharyngeal transit time (PTT) increased and pharyngeal delayed time (PDT) also in 70% of patients. In TBI, PDT in 27% and increased PTT in 42% of patients were found. During follow-up, an improvement was observed in pharyngeal function, with the number of patients with aspiration decreasing, at one year aspiration persisted in 23% of stroke patients (evolution was related to the affected vascular territory: 12% of anterior territory lesions, vs 58% of posterior territory lesions), and 23% in TBI patients. At one year the mean duration of PDT and PTT in stroke patients, albeit reduced, persisted abnormally longer, however in TBI patients the mean duration of these temporal measurements was normal (but 7 patients had a longer temporal measurement) Preface xiii

Conclusion: Swallowing physiology in stroke and in severe TBI greatly improved during follow-up and the number of aspirations decreased progressively. Chapter XIV - The advent of both improved imaging systems and new radioactive agents has increased the effectiveness of nuclear medicine in diagnosing and treating various tumors. Assessment of treatment response and recurrence in the pharyngeal tumors specially the Nasopharyngeal carcinomas (NPC) has been given a considerable attention in the past decade. In this chapter, a review has been made keeping in focus, the utilization of nuclear medicine radiopharmaceutical agents like Thallium-201, Tc-99m MIBI, Tc-99m Tetrofosmin and F-18 FDG PET in the detection and evaluation of disease regression/ progression and recurrence of malignant nasopharyngeal disease. It is concluded that radionuclide imaging offers added value when compared with conventional morphological imaging techniques for the purpose of detection and evaluation of residual and recurrent Nasopharyngeal Carcinomas. Chapter XV - There are studies contributing alternatives to restoring the donor site of free radial forearm flap (FRFF) , indicated for reconstruction of pharyngeal and laryngeal defects, other than split thickness skin graft, such as: full thickness skin grafts, artificial dermis (Alloderm), and negative pressure wound dressing. These techniques are all aimed at establishing thin layer skin coverage. A local bilobed flap, playing a role as a second flap, is applied to cover FRFF donor site and offered as a similar soft tissue. However, the hard scar texture and secondary contracture of the skin graft cause unfavorable sequelae in hand movement and cosmetic results. Limitation of flap size and necrosis of local flaps are often occurred. To simultaneously overcome the important drawback of sacrificing the radial artery in cases of FRFF, methods for restoration of radial artery in the use of anterolateral thigh (ALT) flap were reported. The FRFF donor site is repaired in our series by the ALT, a second fasciocutaneous flap. The latter offers great and similar soft tissue coverage, which, unlike skin grafts, does not result in contracture. Also, there is neither the risk of tendon exposure nor flexor contracture. All major donor site morbidities of the FRFF were solved by the ALT flap coverage, except for abnormal sensations of the radial side of the donor hand. Therefore, the FRFF is a proper choice for pharyngeal and laryngeal defects. When it is chosen for its unique merits, the ALT flap can also serve as an alternative in reconstructing the donor site with least morbidity. Chapter XVI – Objective: Objective is to determine and quantify the production of TNF- in chronic tonsillitis. Material and Methods: The study comprised of 23 patients with chronic tonsillitis, divided in two groups: 10 patients with tonsillar hypertrophy (TH) with average age 9.0 ± 2.7 years, and 13 patients with recurrent tonsillitis (RT) aged 23.1 ± 5.2 years. Highly sensitive labeled streptavidin-biotin horse reddish peroxidase immunohistochemical method (LSAB+/HRP) was used for detection of TNF- producing cells. Quantification of TNF- was made for crypt epithelium, germinative centers, roundness of follicles, interfollicular areas and subepithelial area. Quantification of lymph follicles and germinative centers included: areal (mm2), median optical density (au), circumference (mm), Ferret diameter (mm), and integrated optical density (IOD). Results: Distribution of TNF- producing cells is similar for TH and RT. They are mainly found in subepithelial areas, interfollicular regions, and germinative centers of lymph xiv Aaron P. Nazario and Julien K. Vermeulen follicles, and rarely in crypt epithelium. Numerical density of TNF- producing cells is significantly higher in RT, compared to TH. Conclusion: Quantification of TNF- producing cells confirm domination of cellular Th1 immune response both in TH and RT. Chapter XVII - Peritonsillar abscess (quinsy) is a complication of acute bacterial tonsillitis. Its treatment remains controversial. Needle drainage of the abscess may provide an alternative to incision or tonsillectomy. An important element of controversy is the choice of antibiotics after surgical drainage of the abscess. Results of many studies support the resistance of grown bacteria to many antibiotics and the potential importance of anaerobic bacteria in development of peritonsillar abscesses. Although bacteria grown from the pus vary among the continents, clinical implications resulting from the microbiological studies are similar. Patients with peritonsillar abscesses should be treated with antibiotics effective against both aerobic and anaerobic bacteria. In the routine management of peritonsillar abscess, bacteriologic studies are unnecessary on initial presentation. It is, however, necessary to consider infection with anaerobes. Therefore, penicillin and metronidazole are recommended as the antibiotic regimen of choice in the treatment of peritonsillar abscesses. If this treatment is ineffective, broad-spectrum antibiotics (clinadmycin) should be administered. Chapter XVIII - Tube-fed patients with pharyngeal diseases are receiving enough trace elements by intake of enteral formula including rich trace elements. However, serum trace elements concentration shows a low level even if patients are receiving enough trace elements intake. Since trace elements in serum bind to serum protein, serum trace elements concentration is influenced by serum protein concentration. In addition, synthesis of serum protein in the liver is increased or decreased by malnutrition and inflammation. Especially, tube-fed patients with pharyngeal diseases due to stroke are at high risk of malnutrition and aspiration pneumonia. Therefore, evaluation of serum trace elements concentration has to consider influence of malnutrition and inflammation. The trace elements binding protein of the zinc, iron, and copper is albumin, transferrin, and ceruloplasmin, respectively. Serum trace elements concentration positively correlates to each trace elements binding protein. In the case of malnutrition, serum zinc, iron and copper concentration shows low level according to decrease of each trace elements binding protein concentration. In the case of inflammation, synthesis of albumin and transferrin are decreased, and serum zinc and iron concentration shows low level. In addition, synthesis of ceruloplasmin is increased, and serum copper concentration shows high level. In the patient with inflammation, serum trace elements concentration normalized with decrease of inflammatory response. As for frequency of abnormal serum trace element concentration in patients with pharyngeal diseases who received tube feeding, low serum zinc concentration was 65%, low serum iron concentration was 43%, and high serum copper concentration was 45%. Most of these patients developed hypoalbuminemia and inflammation. In the analysis of nutritional indices that are predictors of serum trace elements in patients with neurological dysphagia on long-term tube feeding, the predictor of serum zinc concentration was albumin, the predictors of serum iron concentration was transferrin and hemoglobin, the predictors of serum copper concentration was ceruloplasmin and C-reactive protein. The serum zinc, iron, and copper concentration were not correlated to each trace elements intake. Preface xv

In conclusion, abnormal serum trace element concentration in the patients with pharyngeal diseases who has received enough trace elements is induced by malnutrition and inflammation. Iron is required for the synthesis of hemoglobin. Zinc is required for immunocompetence and wound healing. Management of trace elements is extremely important to maintain a good condition for patients. To normalize serum trace element concentration, it is a recommend treatment of malnutrition and aspiration pneumonia as well as increase in trace elements intake. Chapter XIX - Isolated uvulitis is significant condition that, like the uvula itself, receives relatively little attention. It is commonly, and at times perhaps erroneously, attributed to bacterial infection. The literature documents many other potential causes of uvulitis including smoke and chemical irritation. A recent case of isolated uvulitis associated with smoking cannabis is discussed. The many infective, traumatic and irritant causes of uvulitis are poorly understood and in need of further research.

Chapter I

Neurological Diseases with Pharyngeal Dysfunction

Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini Department of Neurology, Federal University of São Paulo, Brazil

Abstract

Neurological diseases can affect the pharynx in many different ways, including its motility and somatic sensation. Therefore, these diseases can impair the main pharyngeal functions, causing disorders of swallowing, speech and breathing. The premise of this chapter is to provide dependable and meaningful knowledge as the foundation for clinical work. This chapter is divided into five subsections based on the cardinal manifestation of the neurological diseases. Each subsection contains disciplined presentation of scientific data and lucid description of etiology, pathophysiology, diagnosis and treatment. The first subsection includes disorders of motility, such as motor paralysis and movement disorders. The second subsection comprises disorders of somatic sensation: for instance, pharyngeal anesthesia and neuropathic pain. The third subsection consists of disorders of swallowing, describing the underlying neural mechanisms of dysphagia and aspiration, and their management. The fourth subsection is focused on the disorders of the articulation of speech: dysarthria and anarthria. The fifth subsection emphasizes breathing disorders, such as obstructive sleep apnea of neurological origin. It is important to consider that patients with neurological diseases and pharyngeal dysfunction consult many physicians from different specialties and other professional caregivers because of a multitude of problematic symptoms. In the quest to offer the best assistance, the reader is encouraged to invade those obscure and difficult territories in the domain of neurologists and expand his notion of a disease by knowledge of its current scientific foundations. The comprehensive involvement of two neurologists in writing this chapter has promoted a uniform approach across subject matter that should be pleasing to the reader.

2 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini

1. Introduction

Pharyngeal dysfunction is common in multiple neurological diseases. Appropriate management needs to consider the clinical findings and their response to the treatment in the context of the underlying disease and its natural progression. The study of neurological diseases with pharyngeal dysfunction is divided into five subsections based on their cardinal manifestation. Each subsection describes the etiology, pathophysiology, diagnosis and treatment of the most common neurological diseases with similar pharyngeal dysfunction: disorders of motility, disorders of somatic sensation, disorders of swallowing, disorders of articulation of speech, and disorders of breathing.

2. Disorders of Motility

The impairments of pharyngeal motility can be divided in motor paralysis and movement disorders. They may result from lesions in various parts of the nervous system [1]:

The lower motor neuron: the axons of the large nerve cells in the nucleus ambiguus of the medulla oblongata comprise the efferent motor fibers of the cranial nerves that innervate the pharyngeal muscles. The glossopharyngeal nerve supplies the stylopharyngeus, the pharyngeal branch of the vagus nerve and the cranial part of the accessory nerve constitute the motor pharyngeal plexus that supplies most of the pharyngeal muscles [2]. Together, the neuron, its axons, and the muscle fibers they subserve constitute the motor unit, complete lesions of which result in loss of all movement. The upper motor neuron: the motor neurons in the frontal cortex adjacent to the rolandic fissure connect with the motor nuclei of the brainstem by a system of fibers known as the corticonuclear or corticobulbar tract. The axons subserving the pharyngeal muscles descend from the opercular area of the frontal cortex; traverse the subcortical white matter (corona radiata), genu of the internal capsule, cerebral peduncle, basis pontis (ventral pons); and continue their course in the medulla to reach the nucleus ambiguus. Pharyngeal muscles are bilaterally innervated, stimulation of either the right or left motor cortex results in contraction of these muscles on both sides. Consequently, an isolated unilateral upper motor neuron lesion will affect them little or not at all. Bilateral upper motor neuron paralysis is rarely complete for any long period of time; in this respect it differs from the absolute paralysis due to destruction of the lower motor neuron or interruption of its axons. The basal ganglia (striatum, pallidum, subthalamic nucleus, substantia nigra), cerebellum, and other related areas: these structures are modulation systems of the upper motor neuron function. Each system plays an important role in the control of muscle tone, posture, and coordination of movement by virtue of its connection, via thalamocortical fibers, with descending cortical pathways such as the corticobulbar tract. Neurological Diseases with Pharyngeal Dysfunction 3

As the neuromuscular junction and the muscles are components of the motor unit, failure of neuromuscular transmission and primary striated muscle disease can cause impairment or loss of pharyngeal motor function and will be addressed appropriately.

2.1 Palatal Paralysis

2.1.1 Etiology In general, the commonest known causes of palatal paralysis used to be poliomyelitis affecting the upper part of the nucleus ambiguus in the medulla, diphtheria affecting the nerve endings, and brainstem infarction [3]. Since the development of vaccines and organization of a massive vaccination campaign, the global incidence of poliomyelitis and diphtheria has been greatly reduced. The diseases where the palatal paralysis is not prominent, being only one element of more complex syndromes, such as poliomyelitis and brainstem infarction, will be discussed later in this chapter. Other important causes of palatal paralysis are: tumors, like nasopharyngeal carcinomas; iatrogenic, like adenoidectomy and local anesthesia; and a rare clinical entity called acquired isolated palatal paralysis. The latter has been increasingly recognized as a distinct albeit unusual condition peculiar to pediatric population, encompassing 37 cases reported from 1976 to 2007 [4-6].

2.1.2 Pathophysiology Diphtheria is an acute infectious disease caused by Corinebacterium diphtheriae. Initial infection is often localized in the tonsils and pharynx and it is characterized by the formation of an adherent pseudomembrane of the throat; at this site, the toxigenic strains of the bacteria elaborate an exotoxin, which affects the heart and nervous system in about 20 percent of cases. Typically, the palatal paralysis is the first sign of the nervous system involvement, due to demyelination of nerve endings, and it appears between the fifth and twelfth days of illness. It is followed by ciliary paralysis with loss of accommodation and blurring of vision, but with preserved light reaction, in the second or third week. These findings may clear or a delayed sensorimotor polyneuropathy may develop between the fifth and eighth weeks of the disease, sometimes mimicking the rapidly evolving ascending paralysis of the Guillain-Barré syndrome, including the cerebrospinal fluid (CSF) albuminocytologic dissociation (normal cell count with elevated protein). The neurological symptoms progress for a week or two and, if the patient does not succumb to respiratory or cardiac failure, they stabilize and then improve slowly and more or less completely [7,8]. The squamous cell carcinoma, a malignant tumor of epithelial origin, represents the majority of all head and neck cancers [9]. Although both nasopharyngeal (NPC) and oropharyngeal (OPC) carcinomas can impair palatal motility, NPC seems to be the most common malignant tumor associated with palatal paralysis. A prospective study with 264 patients with NPC, published in 2001, showed that 137 patients (52%) presented with clinical signs of palatal palsy. The nasopharyngoscopic and magnetic resonance imaging (MRI) findings of those patients indicated that most tumors arose from one side of the fossa of Rosenmüller with direct extension to the ipsilateral levator veli palatini muscle [10]. 4 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini

Except from occasional inadvertent surgical lesion of the nerves supplying the soft palate, the iatrogenic causes of palatal paralysis are usually reversible. Pharyngeal surgical procedures, such as adenoidectomy and tonsillectomy, often result in transitory palatal and uvular edema [11]. Dental anesthesia may produce temporary palatal palsy as a consequence of either the simple diffusion of the anesthetic solution or the vasoconstriction-induced ischemic effect of the solution on the vessels feeding the muscles [12]. Although regarded as a sign of lower motor neuron involvement, most of the etiology and pathogenesis of acquired isolated palatal paralysis remain unclear. An acute infective or postinfectious cranial mononeuropathy seems most plausible, as analogous to post- diphtheritic complication and to sporadic reports following infections (herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, hepatitis A virus, parvovirus B19, typhoid fever, cat scratch disease) and inflammatory diseases (Kawasaki disease). The condition is usually benign and self-limiting [4,5]. A review of the literature turned up only one previous report of unilateral palatal paralysis caused by cerebral infarct in the contralateral corticobulbar tract while traversing the corona radiata [13].

2.1.3 Diagnosis The clinical diagnosis of palatal paralysis is based on symptoms and signs of velopharyngeal incompetence (VPI) and motor dysfunction of the soft palate, followed by etiological diagnosis. Historical factors in VPI are primarily related to sudden onset of hypernasality and nasal regurgitation. A unilateral motor unit lesion causes an ipsilateral droop of the palate and flattening of the palatal arch at rest; in addition, the medial raphe deviates toward the normal side on phonation. With a bilateral lesion, the palate cannot elevate on phonation. Preserved function of the tensor veli palatini muscle, innervated by a branch of the trigeminal nerve, may prevent marked drooping of the palate [14]. According to the World Health Organization (WHO), diphtheria cases should be classified as suspected, probable or confirmed. Confirmed cases should be classified as indigenous or imported (infection acquired abroad). The following case definitions should be used in classifying cases [15]:

Suspected case: tonsillitis or nasopharyngitis or laryngitis, plus a pseudomembrane. Probable case: suspected case, with one of the following (recent [< 2 weeks] contact with a confirmed case; diphtheria epidemic currently in the area; stridor; swelling/edema of neck; submucosal or skin petechial haemorrhages; toxic circulatory collapse; acute renal insufficiency; myocarditis and/or motor paralysis one to six weeks after onset; death). Confirmed case: probable case plus isolation of a toxigenic strain of C. diphtheriae from a typical site (nose, throat, skin ulcer, wound, conjunctiva, ear, vagina) or fourfold or greater rise in serum antitoxin, but only if both serum samples were obtained before the administration of diphtheria toxoid or antitoxin.

Diagnosis of head and neck malignancy includes clinical examination, fiberoptic endoscopy, and fine needle aspiration or core biopsy of any neck masses, followed by further examination under general anesthetic with additional biopsies if necessary. Patients with Neurological Diseases with Pharyngeal Dysfunction 5 confirmed malignancy undergo radiological staging by computerized tomography (CT) or MRI [16]. Iatrogenic palatal paralysis diagnosis depends on history and observation. The close temporal correlation between either a medical procedure or a substance administration, both theoretically capable of causing motor dysfunction, and the installation of the palatal palsy, is essential to the diagnosis. Furthermore, observation may demonstrate the usual transitory character of this condition. Establishing idiopathic etiology of acquired isolated palatal paralysis requires exclusion of other potentially dangerous conditions, such as tumors, ischemia and demyelination. Cranial MRI with angiography is the modality of choice to rule out these lesions. Besides, all routine hematological investigations, including viral serology and other microbiological studies, must be performed. In view of the self-limiting benign reversible course, invasive examinations like lumbar puncture are unwarranted. Absence of symptomatic improvement after 2 weeks, recurrence or evidence of neurological involvement elsewhere should prompt further investigation [4].

2.1.4 Treatment The treatment of palatal paralysis should be directed toward the etiological factor whenever possible. In the case of an irreversible lesion, symptomatic treatment for VPI will be required. Current methods of rehabilitation of VPI include speech therapy, palatal prosthetic augmentation, and surgical therapy, which are addressed in more detail in ―Disorders of speech articulation‖. If diphtheria is strongly suspected, WHO recommends that specific treatment with antitoxin and antibiotics should be initiated immediately while bacteriological investigations are still pending. It is generally agreed that the administration of antitoxin within 48 hours of the earliest symptoms of the primary diphtheritic infection lessens the incidence and severity of the neurological complications. Antibiotic therapy is also required to eradicate the organism and prevent spread. The recommended dose regimens are as follows [15]:

Antitoxin (tonsillar 15,000–25,000U; pharyngeal 20,000–40,000U; IM/IV); Penicillin G (children 25,000–50,000U/kg/d; adults 600,000U twice daily) or parenteral erythromycin (40–50mg/kg/d; maximum of 2g/d) until the patient can swallow comfortably, at which point penicillin V (125–200mg four times daily) or oral erythromycin in four divided doses may be substituted and continued for 14 days.

If the palatal paralysis is caused by a primary NPC or OPC that can be excised with an appropriate margin of normal tissue without resulting in major functional compromise, the surgery may be the therapy of choice. Non-surgical treatment (radiotherapy with or without chemotherapy) should be offered to patients if survival rates are comparable with surgical resection. Following surgical resection of the primary tumor, adjuvant postoperative radiotherapy should be considered where indicated. NPC and OPC management is addressed in more detail elsewhere [16]. 6 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini

Acquired isolated palatal paralyses of iatrogenic or idiopathic etiology are usually temporary and fully reversible. There is no specific treatment for both conditions other than close observation [4-6, 11,12].

2.2 Pharyngeal Paralysis

2.2.1 Etiology The etiology of pharyngeal paralysis may be classified according to the localization of the disease process and the resulting syndrome [1,14]:

Bilateral upper motor neuron lesions are usually due to vascular (multiple lacunar infarcts), demyelinating (multiple sclerosis), degenerative (motor neuron disease, progressive supranuclear palsy), neoplastic (mesencephalic or pontine astrocytomas), traumatic (craniocerebral trauma), or developmental diseases (Worster-Drought syndrome, congenital bilateral perisylvian syndrome). Nuclear lesions of the nucleus ambiguus can occur with vascular (medullary infarct), degenerative (motor neuron disease, Kennedy‘s disease), neoplastic (medullary astrocytomas), infectious (poliomyelitis), traumatic and developmental diseases (syringobulbia). Intracranial skull base lesions are often due to inflammatory (polyradiculoneuritis, meningitis), neoplastic (extramedullary tumors), vascular (aneurysms) and developmental diseases (Arnold-Chiari malformation). Jugular foramen lesions can be a manifestation of neoplastic (tumor of jugular bulb), vascular (internal jugular vein thrombosis), traumatic (basilar skull fractures), and infectious diseases (abscess). Retropharyngeal or retroparotid or posterior lateral condylar spaces lesions are usually due to neoplastic (tumor of parotid or skull base), vascular (carotid aneurysm, including dissection) and infectious diseases (abscess). Neuromuscular junction lesions can occur with post-synaptic (myasthenia gravis) or presynaptic involvement (Eaton-Lambert myasthenic syndrome, botulism). Primary striated muscle lesions are often due to inflammatory (dermatomyositis, polymyositis, inclusion body myopathy) and degenerative diseases (myotonic dystrophy, oculopharyngeal muscular dystrophy).

2.2.2 Pathophysiology In bilateral upper motor neuron lesions, the patient may have had a clinically imperceptible lacunar infarct (arteriosclerosis of a small penetrating cerebral artery) or demyelinating lesion (immunological destruction of the myelin sheaths of nerve fibers) at some time in the past, affecting the corticobulbar fibers on one side. Should another lesion then occur, involving the other corticobulbar tract, and his pharynx immediately becomes dysfunctional [1]. When the signs of upper motor neuron lesions are slowly progressive, motor neuron disease (loss of nerve cells in the motor cortex found in amyotrophic lateral sclerosis – ALS, and in primary lateral sclerosis), progressive supranuclear palsy Neurological Diseases with Pharyngeal Dysfunction 7

(accumulation of neurofibrillary tangles and neuropil threads with tau protein in the basal ganglia, pontine tegmentum, medulla, and oculomotor and dentate nuclei) or upper brainstem astrocytomas (relatively slow-growing tumors that can infiltrate the corticobulbar tracts) must be considered in the differential diagnosis [1]. Craniocerebral trauma can cause brain swelling, diffuse axonal injury, bilateral contusions and hemorrhages that impair the upper motor neuron function [1]. Worster-Drought syndrome is caused by agenesis or hypogenesis of corticobulbar tracts and congenital bilateral perisylvian syndrome is due to a neuronal migration disorder characterized by disorganization of motor cortical architecture with aberrant columnar and laminar neuronal arrangements [17]. The nucleus ambiguus is located at the lateral medullary tegmentum, supplied by the posterior inferior cerebellar artery (PICA), a branch of the vertebral artery. Acute nuclear lesions are more often due to vascular diseases, generally vertebral artery thrombosis with PICA occlusion, but they can occur with isolated PICA occlusion, and rarely with vertebral artery occlusion below the origin of the PICA [1,14]. A gradually progressive nuclear lesion is usually caused by motor neuron disease (loss of nerve cells in the motor nuclei found in ALS and progressive bulbar palsy), Kennedy‘s disease (X-linked bulbospinal muscular atrophy due to CAG expansion in the androgen receptor gene on the short arm of the X chromosome), syringobulbia (pathological cavity often found in the lateral medullary tegmentum), or medullary astrocytomas (tumor infiltration of the motor nuclei) [1,14]. The syndrome of acute anterior poliomyelitis is the result of infection by some enteroviruses (poliovirus, enterovirus 70 and 71, Coxsackie virus A and B) and arboviruses (West Nile virus, Japanese encephalitis virus). In only a small fraction of infected patients, motor nuclei of the brainstem and anterior horn of the spinal cord are invaded, where the nerve cells are destroyed and phagocytosed by microgliacytes (neuronophagia) [18-20]. The lower cranial nerves are frequently affected before they exit the skull. Pharyngeal paralysis can be a sign of acute polyradiculoneuritis (pharyngeal-cervical-brachial variant of Guillain-Barré syndrome) or of chronic inflammatory demyelinating polyradiculopathy (CIDP), both due to an immune response to foreign antigens misdirected to gangliosides in the nerve sheath, especially the anti-GT1a and anti-GQ1b IgG antibodies [21,22]. Intracranial skull base lesions may be caused by chronic leptomeningitis (tuberculous, fungal, and carcinomatous meningitis) or pachymeningitis (sarcoidosis, rheumatoid arthritis, syphilis), where the inflammatory thickening of the meninges infiltrates the cranial nerves [1]. Among the intracranial extramedullary tumors that involve the cranial nerves, the most common is the meningioma, a benign tumor that is twice more frequent in old women. Some are hereditary and the most frequent genetic defects of meningiomas are mutations in the neurofibromatosis 2 gene on chromosome 22q, also known as the merlin gene [1,23]. Aneurysms of posterior circulation account for 10% to 15% of all intracranial aneurysms, and the origins of the PICA is the third most common site of posterior circulation aneurysms, where the cranial nerves may be stretched and distorted [24]. The commonest lesion at the foramen magnum is downward herniation of a tongue of cerebellar tissue, also termed the Arnold-Chiari malformation. It generates craniospinal pressure dissociation with consequent distortion of the brainstem, traction on cranial nerves or indentation of the brainstem by vascular loops [1,25]. 8 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini

Basically, the jugular foramen contains the origin of the internal jugular vein and the 9th, 10th and 11th cranial nerves. This foramen is frequently infiltrated by paragangliomas (potentially malignant tumors of chemoreceptor organs located in the glomus jugulare, carotid body and the vagus nerve); neurinomas of the 9th, 10th and 11th cranial nerves (benign tumors of Schwann cells that are occasionally part of neurofibromatosis); meningiomas and NPC. Metastatic skull base neoplasms are often due to prostrate, breast and lung cancers [1,14]. Central venous catheters, deep neck infections and head and neck cancer are the most common causes of internal jugular vein thrombosis; the cranial nerves are affected in 6% of the cases [26]. Closed head injury may result in jugular foramen bony disruption and impingement of one or more cranial nerves or nerve edema and/or hematoma [27,28]. The retropharyngeal or retroparotid or posterior lateral condylar spaces lesions are often due to neoplastic diseases that may implicate the sympathetic nerves and the 9th, 10th, 11th and 12th cranial nerves. Benign pleomorphic adenomas account for 63% of parotid tumors and they grow to be very large; NPC, OPC and carotid body paraganglioma frequently invade these spaces too [29]. A dissection of the internal carotid artery (ICA), with or without aneurysm formation, may compress the sympathetic and lower cranial nerves; spontaneous dissection of the ICA affects these nerves in about 12% of the cases [30]. Acute upper airway infection can be complicated by retropharyngeal or parapharyngeal abscess, affecting one or more cranial nerves [31]. The motor nerve terminal synthesizes acetylcholine (ACh), which is stored in vesicles. After nerve depolarization, ACh vesicles binds to the nerve membrane and packets of ACh are released at the nerve ending, diffuse into the narrow synaptic cleft, and combine with ACh receptors (AChR) on the muscle membrane. The most frequent cause of neuromuscular junction disorder is myasthenia gravis (MG), a disease where humoral antibodies directed against protein components of AChR block the binding of ACh to the receptor, may induce AChR endocytosis and degradation, and may cause complement-mediated destruction of the post-synaptic folds [32]. Some instances of seronegative MG are due to antibody production against a muscle-specific kinase (MuSK), an enzyme that plays a role in supporting the normal structure of the postsynaptic membrane and in the arrangement of AChR [33,34]. In Lambert-Eaton myasthenic syndrome, antibodies against voltage-gated calcium channels reduce the number of functioning channels in the motor nerve terminal, consequently reducing the presynaptic release of ACh [32]. Botulism is caused by the exotoxin of Clostridium botulinum, a protease that cleaves proteins of the synaptic fusion complex, thus irreversibly preventing the normal exocytosis of ACh. Poisoning of botulinum toxin is most often due to inadequate conservation and preparation of contaminated food; very rarely, the source is a contaminated wound or a complication of the therapeutic use of the toxin. The action of the toxin usually begins at the brainstem and travels downward the spinal cord [35- 37]. Finally, pharyngeal paralysis may be an early and prominent sign of an idiopathic inflammatory myopathy. Almost half of patients with polymyositis (PM) and dermatomyositis (DM) have antibodies against cytoplasmic transfer ribonucleic acid (tRNA) synthetases (anti-Jo1). Other less common antibodies are directed against a cytoplasmic ribonucleoprotein complex called the signal recognition particle (anti-SRP), found in about 5% of the idiopathic inflammatory myopathies, or against a protein complex that is a nuclear Neurological Diseases with Pharyngeal Dysfunction 9 helicase (anti-Mi2). In DM, the immune response is predominantly humoral and is directed primarily against intramuscular blood vessels; in PM, the response is composed of cytotoxic T cells that enclose and invade viable muscle fibers accompanied by macrophages [38]. Inclusion body myopathy (IBM) is the third major form of idiopathic inflammatory myopathy, predominates in adult males and is usually sporadic. A rare autosomal recessive IBM is caused by a mutation in the glucosamine (UDP-N-acetyl)-2-epimerase/N- acetylmannosamine kinase (GNE) gene on chromosome 9p; defects of this unusual bifunctional protein reduce the number of sugar and sialic acid residues on muscle proteins, increasing the susceptibility of the muscle membrane to injury [39,40]. The disease mechanism in sporadic IBM is unclear, but some authors suggest that two processes might occur in parallel: a primary immune process due to cytotoxic T cells and a non-immune process characterized by vacuolization and intracellular accumulation of amyloid-related molecules, probably due to major histocompatibility complex class I antigens induced stress [40]. Myotonic dystrophy is the most common adult form of muscular dystrophy and its specific molecular defect is an unstable trinucleotide sequence (CTG) on chromosome 19q that is longer in affected individuals with an autosomal dominant pattern. The mutation resides within the myotonic dystrophy protein kinase gene and causes an intranuclear accumulation of the expanded RNA sequences, believed to alter RNA binding proteins, thereby perturbing the expression of many genes [38]. Oculopharyngeal muscular dystrophy is usually an autosomal dominant disease of late onset, affecting French-Canadian families predominantly. The gene defect is a nucleotide expansion in the polyadenylate binding protein nuclear 1 gene on chromosome 14, and it was proposed that the resulting polyalanine domains polymerize and accumulate as intranuclear inclusions, thus interfering with gene expression [41].

2.2.3 Diagnosis The clinical diagnosis of pharyngeal paralysis is based on symptoms and signs of dysarthria, dysphagia and weakness of the pharynx, followed by etiological diagnosis. Dysarthria is usually minimal unless there is also weakness of the soft palate or larynx. Dysphagia is marked only in acute unilateral or in bilateral lesions, but without the tendency to greater difficulty with liquids and to nasal regurgitation that occurs with palatal weakness. Examination of the pharynx includes the observation of the contraction of the pharyngeal muscles on phonation, notation of the elevation of the larynx on swallowing, and testing the pharyngeal gag reflex. A unilateral motor unit lesion may cause motion of the pharyngeal wall toward the nonparalyzed side at the beginning of phonation or on testing the gag reflex, a curtain movement called Vernet‘s rideau phenomenon. The elevation of the larynx may be absent on one side in unilateral lesions, and on both sides in bilateral lesions. Spontaneous coughing and the cough reflex may be impaired. Bilateral complete vagal paralysis is incompatible with life [14]. Bilateral upper motor neuron lesions result in the syndrome of pseudobulbar palsy: in this condition, the palatal and pharyngeal gag reflexes are retained or increased; emotional control is impaired with spasmodic crying and laughing (pseudobulbar affective state), and sometimes the periodic breathing of Cheyne-Stokes accompanies the syndrome. Abrupt onset of this syndrome points to a cerebrovascular disease, usually multiple lacunar infarcts, which 10 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini can be reliably confirmed with a cranial MRI. Initially, lacunes are seen on the MRI as deep oval or linear areas of T2, FLAIR, and especially, diffusion weighted image signal abnormality; later they become cavitated [1]. Acute onset of pseudobulbar palsy may be an attack of multiple sclerosis (MS), whose diagnosis is based upon clinical dissemination of the disease progress in time and in space (two or more attacks and objective evidence of two or more lesions) when other diagnoses had been ruled out by appropriate tests. According to the revised McDonald criteria for MS, sometimes temporal and/or spatial dissemination need to be demonstrated by abnormalities detected with cranial and spinal MRI (at least one gadolinium-enhanced lesion on T1 or at least nine hyperintense lesions on T2; at least one juxtacortical lesion; at least one infratentorial lesion; at least three periventricular lesions) associated with CSF analysis (oligoclonal IgG bands) and visual evoked potentials (prolonged latency of the first positive peak or P100) [42]. In the revised El Escorial criteria for the diagnosis of ALS, the most common form of motor neuron disease, the required clinical signs of upper (UMN – such as pseudobulbar palsy and pyramidal signs) and lower motor neuron (LMN – such as atrophy and fasciculation) lesions associated with the electromyography (EMG) signs of chronic and active denervation (fibrillation potentials and positive sharp waves) are studied in four body regions (the cranial, cervical, thoracic and lumbosacral regions) and then categorized in four degrees of certainty: clinically definite diagnosis requires UMN and LMN signs in three regions; clinically probable ALS requires the same signs in two regions with some UMN signs rostral to the LMN signs; clinically probable EMG-supported ALS requires UMN and LMN signs in one region or UMN signs alone in one region, and EMG signs in at least two limbs; and clinically possible ALS requires UMN and LMN signs in one region or UMN signs alone in at least two regions or LMN signs rostral to UMN signs. Other diagnoses must be excluded by appropriate tests [43]. An international workshop proposed clinical research criteria for the diagnosis of progressive supranuclear palsy (PSP) and categorized them in three levels of certainty: possible PSP is a gradually progressive disease with onset at age 40 or later, including either vertical supranuclear gaze palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of onset; probable PSP needs the presence of both vertical supranuclear gaze palsy and prominent postural instability with falls in the first year of onset; definite PSP is a possible or probable PSP with typical distribution of neurofibrillary tangles and neuropil threads. There must be no evidence of other disease that could explain these features, and other supportive criteria may be present, such as symmetric proximal akinesia or rigidity, abnormal neck posture, inadequate response to levodopa, and early onset of dysphagia, dysarthria and cognitive impairment [44]. In most patients with astrocytomas of the brainstem, the initial manifestation is palsy of one or more cranial nerves, usually the sixth and seventh on one side, followed by long tract signs. Diffusely infiltrating tumors shows a mass effect with hypointense signal on T1- weighted MRI and heterogeneously increased T2 signal, while focal or nodular tumors tend to occur in the dorsal brainstem and often protrude in an exophytic manner [1,45]. History of trauma, bogginess of the periorbital tissues (raccoon eye) or temporal or postauricular areas (Battle sign), bleeding or CSF leakage from the nose or ear, extensive conjunctival edema and hemorrhage suggest the diagnosis of craniocerebral trauma, which can be confirmed with Neurological Diseases with Pharyngeal Dysfunction 11 a cranial CT or MRI [1]. Among the congenital pseudobulbar palsies, the Worster-Drought syndrome spares involuntary orofacial movements and may show bilateral perisylvian polymicrogyria and partial agenesis of the corpus callosum in MRI, whilst the congenital bilateral perisylvian syndrome includes delayed milestones of development, learning disability and epilepsy, and may show gray matter heterotopia in MRI [17]. Lesions of the nucleus ambiguus are usually of vascular origin. The lateral medullary syndrome or Wallenberg‘s syndrome is characterized by ipsilateral flaccid paralysis of soft palate, pharynx and larynx; loss of pain and temperature in the ipsilateral face and contralateral body; ipsilateral central Horner‘s syndrome; cerebellar ataxia of ipsilateral limbs with nystagmus and lateropulsion. A cranial MRI with angiography is the method of choice to confirm the diagnosis [1,14]. The diagnosis of Kennedy‘s disease is suspected when a muscular atrophy with prominent bulbar signs is associated with gynecomastia, oligospermia, diabetes, and a X-linked pattern of inheritance, and it can be confirmed by genetic testing for the lengthened trinucleotide sequence [46]. The neurological disturbances of syringobulbia are characteristically unilateral and depend on the extension of the destructive cavitation and consequent gliosis. Therefore, the syndrome of syringobulbia may include nystagmus; ipsilateral facial analgesia and thermal anesthesia; ipsilateral palatal, pharyngeal, laryngeal and tongue weakness with hemiatrophy. This condition can be reliably confirmed with a cranial MRI [1,47]. According to the WHO, a suspected case of poliomyelitis is defined as a child less than 15 years of age presenting with acute flaccid paralysis (AFP), or as any person at any age with paralytic illness if poliomyelitis is suspected. As a standard procedure, two stool specimens are collected from an AFP case within 14 days of paralysis onset for viral isolation with specific immune serum or polymerase chain reaction (PCR) testing. Additional stool specimens from up to five close contacts are taken if this is not possible [48]. Viral infections of the central nervous system are usually accompanied with meningitis and/or encephalitis, hence the benefits of performing a cranial CT or MRI scan in patients with AFP are double: the scan may show changes in the basal ganglia and thalamus suggestive of West Nile virus or Japanese encephalitis virus infection; and the scan rule out the presence of an expansive lesion or obstructive hydrocephalus, both of which make performance of a lumbar puncture dangerous. CSF PCR testing is useful and sensitive for enteroviruses and Japanese encephalitis, while West Nile CNS viral infection is diagnosed by detection of specific IgM antibody in CSF using an ELISA technique [49]. The Guillain-Barré syndrome is characterized by acute onset of ascending tetraparesis and areflexia; and the pharyngeal-cervical-brachial variant of this syndrome has acute progression of oropharyngeal, neck and shoulder weakness, absence of sensory disturbances, and preserved muscle stretch reflex in the legs. Both are associated with CSF albuminocytologic dissociation, and EMG signs of denervation and decreased conduction velocity in nerves [21]. Chronic or relapsing onset of this syndrome, reaching a nadir in more than 8 weeks, is known as CIDP [22]. Chronic lymphocytic meningitis that is accompanied by cranial nerve palsies often turns out to be tuberculous if the patient is febrile and the CSF glucose is low; it is likely to be neoplastic if the patient is afebrile and the CSF glucose is normal or mildly decreased. Concentrated cytologic preparations usually permit identification of tumor cells, bacteria and fungi, and growth of infectious agents in culture media [1]. The 12 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini diagnosis of pachymeningitis is suggested by thickening of the dura on enhanced CT scans and MRI, and may be confirmed with a meningeal biopsy [1,50]. The prominent vascularity and tendency to calcify of meningiomas are reflected by homogeneous contrast enhancement on CT and MRI or by tumor blush on angiography; calcification at the outer surface or heterogeneously throughout the mass is common [1]. Although aneurysms of the posterior circulation are definitely diagnosed with conventional angiography, the eventual compression of the cranial nerves is better seen with a cranial MRI [1]. Signs and symptoms of Arnold- Chiari malformation may be those of increased intracranial pressure (exertional occipital pain); progressive cerebellar ataxia; downbeating nystagmus; disorders of the lower cranial nerves; progressive spastic tetraparesis; or cervical syringomyelia. This malformation can be confirmed with a CT or MRI at the level of the magnum foramen [1,25]. The jugular foramen syndrome or Vernet‘s syndrome is characterized by ipsilateral weakness of the soft palate, pharynx, larynx, sternocleidomastoid and trapezius muscles. This syndrome usually has a progressive pattern caused by neoplastic disease that is better addressed with a head and neck cancer diagnostic approach, including contrast-enhanced cervical and cranial CT and/or MRI [14,16]. Abrupt onset of this syndrome points to a vascular disease, but the majority of patients with internal jugular vein thrombosis (IJVT) remain asymptomatic and the signs of IJVT can often be very subtle, such as pain and swelling at the angle of the jaw and a palpable cord beneath the sternocleidomastoid muscle. History of central venous catheterization, acute oropharyngeal infection or head and neck cancer helps not to overlook the diagnosis. Septic IJVT secondary to oropharyngeal infection is known as Lemierre‘s syndrome and is usually associated with fever, leukocytosis, neck pain, mass or swelling, cord sign and sepsis. The diagnosis of IJVT is established with ultrasonography (intraluminal low amplitude echoes, loss of venous pulsation and respiratory rhythmicity, distended and incompressible vein), enhanced CT scan (low density lumen, vein engorgement and enhancement of the venous wall), venous phase of arteriography, and MRI venography [26,51]. History and/or signs of trauma suggest the diagnosis of jugular foramen bony disruption that is confirmed with a cranial CT or MRI [27,28]. The retropharyngeal space syndrome or Villaret‘s syndrome is characterized by ipsilateral palatal, pharyngeal and laryngeal weakness and sensory loss, ipsilateral loss of taste on posterior third of tongue, ipsilateral sternocleidomastoid, trapezius and tongue muscles weakness, and ipsilateral Horner syndrome. The retroparotid space syndrome or Tapia‘s syndrome is characterized by ipsilateral palatal, pharyngeal, laryngeal and tongue weakness and ipsilateral Horner syndrome; an ipsilateral sternocleidomastoid and trapezius muscles weakness is sometimes present. The posterior lateral condylar syndrome or Collet- Sicard‘s syndrome is characterized by ipsilateral palatal, pharyngeal and laryngeal weakness and sensory loss, ipsilateral loss of taste on posterior third of tongue, and ipsilateral sternocleidomastoid, trapezius and tongue muscles weakness. Similarly to the jugular foramen syndrome, these three syndromes often have a progressive course due to an underlying neoplastic disease [14]. Therefore, a complete evaluation for head and neck cancer is usually necessary, including cervical and cranial CT and/or MRI [16]. Sudden onset of one of these three syndromes directs to a vascular origin, but some cases of extracranial internal carotid artery dissection (ICAD) are asymptomatic or cause only mild transient symptoms and remain undiagnosed. Although the history of any mechanical neck Neurological Diseases with Pharyngeal Dysfunction 13 trauma or stress helps not to overlook the diagnosis, spontaneous ICAD caused by a previously unknown underlying arteriopathy can occur. Generally, pain is the initial symptom of ICAD: an ipsilateral throbbing head, neck and/or facial pain that sometimes precede a cerebral ischemic event. Other symptoms of ICAD include ipsilateral amaurosis fugax, neck swelling, pulsatile tinnitus, and scintillating scotoma. Signs associated with ICAD include contralateral hemiparesis, ipsilateral cervical bruit, neck hematoma and/or ecchymosis, massive epistaxis, spine and/or skull injuries [52]. Doppler ultrasonography can currently be used for the initial assessment of patients with suspected ICAD, where an abnormal blood flow pattern is shown in up to 90% of the confirmed cases with a false-negative rate of up to 31% [53]. Consequently, duplex scanning should always be followed by another imaging modality: helical CT angiography (changes in the caliber or the cross section of the vessel lumen), MRI angiography (irregular vessel margins, filling defects, extravasation of contrast, vascular occlusion, caliber changes of the vessel), or conventional angiography (pathognomonic intimal flap or double lumen) [54]. The history of previous acute upper airway infection and identification of a neck mass in the retropharyngeal and/or parapharyngeal spaces suggests the diagnosis of a deep neck abscess. Ultrasonography is a useful screening tool for some neck abscesses; CT is the most widely used imaging modality for deep neck infections; and MRI may be useful to delineate soft tissue planes and define abscess extension in difficult cases [31]. Albeit the first descriptions of the Vernet‘s and Collet-Sicard‘s syndromes were of traumatic origin, these syndromes are rarely caused by skull base fractures, in most instances associated with occipital condyle fractures [55]. The group of diseases affecting the neuromuscular junction exhibits a fluctuating weakness and fatigability of muscle. Combined weakness of the ocular, facial and bulbar muscles associated with normal pupillary responses to light and accommodation is virtually diagnostic of myasthenia gravis (MG). There are two special clinical tests for MG: the icepack test (improvement in eyelid drooping after covering the eye with an icepack for two minutes) and the Tensilon test (improvement in any weak area of the body after administration of edrophonium or any other anticholinesterase inhibitor). Decrementing response on repetitive nerve stimulation at a rate of 3Hz and reversal of this response by the Tensilon test generally confirms MG, but it can be normal in patients with mild or purely ocular disease. Single fiber EMG is the most sensitive method of detecting the defect in neuromuscular transmission and shows increased jitter in some muscles in almost all patients with MG. This finding is not specific of MG, but normal jitter in a weak muscle excludes neuromuscular junction disease as the cause of the weakness [32]. The detection of anti- AChR and/or anti-MuSK antibodies provides a sensitive and highly specific test for the diagnosis of MG. It has been proposed that patients with anti-MuSK antibody, mostly women, have a special clinical syndrome of prominent oculobulbar weakness, often with persistently severe disease and respiratory crisis [33,34]. Contrasting typical MG, Lambert-Eaton myasthenic syndrome (LEMS) is characterized by symmetrical weakness and fatigability of muscles of the trunk, girdles, and lower extremities combined with autonomic disturbances. Although ptosis, diplopia, dysarthria, and dysphagia may occur, presentation with these symptoms is definitely uncommon. In direct contrast to MG, there may be a temporary increase in muscle power during the first few 14 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini contractions, which can be confirmed by EMG: a single stimulus of nerve may evoke a low- amplitude muscle action potential (normal or nearly so in MG), whilst at the repetitive nerve stimulation rate of 50Hz or with strong voluntary contraction there is an incrementing response. In LEMS, the response to the Tensilon test is poor or at least unpredictable. The serologic detection of antibodies against voltage-gated calcium channels confirms the diagnosis and should lead to a search for an occult tumor, particularly oat-cell carcinoma of the lung [32]. Botulism symptoms usually appear within 12 to 36h of ingestion of the tainted food with anorexia, nausea, and vomiting occurring in most patients. Neurological disease always manifest initially with blurred vision, diplopia, and unreactive pupils, followed closely by bulbar paralysis with an invariable symmetric descending progression. The clinical diagnosis can be confirmed with EMG, whose findings are similar to what was described for LEMS. A normal Tensilon test helps to differentiate botulism from MG and a normal CSF analysis helps to distinguish it from Guillain-Barré syndrome. Laboratory confirmation is done by demonstrating the presence of the toxin in serum, stool, or food, or by culturing C. botulinum from stool, food, or a wound; the standard laboratory diagnostic test for clinical specimens or culture isolates is the mouse bioassay, in which type-specific antitoxin protects mice against any botulinum toxin present in the sample [36]. Polymyositis (PM) and dermatomyositis (DM) are characterized by a subacute symmetrical painless weakness of proximal limb and trunk muscles. When the patient is first seen, the cervical, pharyngeal, laryngeal, and striated esophageal muscles may be involved as well, but ocular muscles are not affected. If not treated, the muscle weakness and atrophy progress and can result in a fibrous contracture of the involved muscles. In both PM and DM, serum levels of creatine kinase and other muscle enzymes (lactic dehydrogenase, aldolase, and aminotransferases) are elevated, and EMG abnormalities of myopathic type (fibrillation potentials, positive sharp waves, polyphasic units, myotonic activity) are observed. Muscle biopsy may show muscle fiber necrosis with an inflammatory reaction (cytotoxic T cells accompanied by macrophages) and muscle regeneration (proliferating sarcolemmal nuclei, basophilic sarcoplasm, new myofibrils) usually found in PM; or it may show perifascicular muscle fiber atrophy, perimysial inflammatory reaction (increased B cells) and intramuscular vasculitis (endothelial tubular aggregates and fibrin thrombi occlusion) often found in DM. Dermatological alterations that are only found in DM: lilac-colored change in the skin over the eyelids, on the bridge of the nose, on the cheeks, and over the forehead (heliotrope); red raised papules over exposed surfaces such as the elbows, knuckles, and distal and proximal interphalangeal joints (Gottron‘s papules). Specific clinical presentations are associated with certain antibodies: anti-Jo1 with the synthetase syndrome (interstitial lung disease, arthritis, Raynaud phenomenon, thickening of the skin of the hands or mechanic‘s hands); anti-SRP with acute onset disease plus heightened risk of cardiac involvement; anti-Mi2 with rash over the neck and upper shoulders, known as the V sign [38]. Differently from PM and DM, IBM is a slowly progressive asymmetrical myopathy that affects proximal and distal muscles, and involvement of quadriceps and deep finger flexors are clues to early diagnosis; facial and pharyngeal muscle weakness is common and sometimes prominent. In addition, IBM has a distinctive histophatology characterized by autoimmune inflammatory features combined with degenerative features, such as vacuoles, filamentous inclusions and accumulation of Neurological Diseases with Pharyngeal Dysfunction 15 amyloid-related proteins. Serum muscle enzymes elevation and EMG with myopathic pattern are similar to PM and DM [40]. In most instances of myotonic dystrophy, four striking attributes of the disease can be found with variable expression: ptosis with facial and distal limb weakness (hands, forearms extensors and pretibial muscles); myotonia (prolonged idiomuscular contraction following brief percussion or electrical stimulation and in delay of relaxation after strong voluntary contraction, both easily elicited in the hands and tongue); cardiac conducting apparatus abnormalities (bradycardia and prolonged P-R interval); and dystrophic changes in other tissues (cataracts in 90% of the cases, gonadal deficiency, insulin resistance). Progressive frontal baldness and exaggerated forward curvature of the neck (swan neck) are characteristic features in both men and women, and sometimes ptosis and facial atrophy are associated with teeth malocclusion, resulting in an expressionless hatchet face. Definite diagnosis is given by detection of the myotonic dystrophy protein kinase gene mutation [38]. Diagnostic criteria for oculopharyngeal muscular dystrophy (OPMD) include: autosomal dominant inheritance, ptosis with late ophthalmoplegia, symptomatic dysphagia, and detection of the polyadenylate binding protein nuclear 1 gene trinucleotide expansion. OPMD is characterized histologically by unique filamentous inclusions within skeletal muscle fibers observed by electron microscopy; other typical, but not specific, finding in muscle biopsy specimens of OPMD patients is the presence of basophilic-rimmed vacuoles of autophagic nature. Muscle biopsy is only warranted in those individuals with normal results in molecular genetic testing [41].

2.2.4 Treatment Alike palatal paralysis, the treatment of pharyngeal paralysis should be directed toward the etiological factor whenever possible. In the case of an irreversible lesion, symptomatic treatment for dysphagia and dysarthria will be required. Current methods of rehabilitation of dysphagia and dysarthria include behavioral therapy, medical interventions, and surgical therapy. Disorders of swallowing and articulation of speech and their management are addressed in more detail later in this chapter. Rarely, the patient who has had a transient ischemic attack or an atherothrombotic or embolic infarction is brought to medical attention within a few minutes of onset. After recognition of stroke signs and symptoms, the emergency medical services should be activated for initial assessment, management, and rapid transport to closest appropriate facility capable of treating acute stroke. Hypotension and excessive blood pressure reduction must be avoided in the acute phase. Once a stroke has developed fully (after 24 hours from onset), none of the therapeutic measures to restore the circulation and arrest the pathologic process (thrombolytic agents, mechanical lysis, surgical revascularization) has proved to be consistently effective in restoring the damaged encephalic tissue to a functional state. The oral administration of aspirin at the initial dose of 325mg within 24 to 48 hours after stroke onset is recommended for treatment of most patients [56]. In all but the most seriously ill patients, physical therapy and rehabilitation should ideally begin within a few days of the stroke. An assessment for swallowing difficulty should be made early during recovery and dietary adjustments made if there is a risk of aspiration. Since the primary objective in the treatment of functional stroke patients is prevention, efforts to control the risk factors must continue. Preventive measures for atherothrombotic disease include: aspirin, cholesterol- 16 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini lowering drugs, cautious alleviation of hypertension, smoking cessation, and endarterectomy and angioplasty with stenting for symptomatic carotid stenosis. There is no unanimity of opinion about the management of asymptomatic carotid stenosis and the use and timing of anticoagulation with warfarin after an embolic stroke. The long-term use of anticoagulants has proved to be effective in the prevention of embolism in cases of atrial fibrillation, myocardial infarction, cardiac valve prosthesis, severely stenotic cerebral vessel and certain blood disorders [1]. The treatment of MS can be divided in three categories: acute, disease-modifying and symptomatic treatments. During acute attacks, administration of high doses of corticosteroids, such as methylprednisolone 500 to 1000mg daily for 3 to 5 days, is the routine therapy. There is no evidence of major differences in the efficacy of methylprednisolone treatment given intravenously or orally in terms of clinical efficacy or side effects, but prolonged oral treatment may possibly be associated with a higher prevalence of side effects. Although generally effective in the short term for relieving symptoms, corticosteroid treatment does not appear to have a significant impact on long-term recovery [57,58]. Disease-modifying agents include: interferon beta 1a and 1b, glatiramer acetate, mitoxantrone, and more recently natalizumab. At first sight, comparisons between immunomodulators other than mitoxantrone show that the most effective is natalizumab, both in terms of relapse rate reduction and halting disability progression [59]. However, the comparison between natalizumab and other disease-modifying agents was too inconsistent on the relative risk and the number needed to treat analysis to be a reliable guide to relative efficacy [60]. Symptomatic treatment is an essential component of the overall management of MS to eliminate or ameliorate symptoms affecting the patients‘ functional abilities impairing quality of life. It includes speech and functional swallowing therapies associated with the treatment for spasticity, fatigue and tremor [61]. Riluzole is the only drug approved to specifically treat ALS in most countries and when used at the dose of 50mg twice daily it may increase survival by 2 to 3 months. Riluzole is believed to reduce damage to motor neurons by decreasing the synaptic release of glutamate [62]. Symptomatic management is the mainstay of ALS patient care and multidisciplinary teams of health care professionals best provide it. Medications help reduce fatigue, spasticity, and excess saliva, and other symptoms; physical, speech, functional swallowing, nutritional, and respiratory therapies can enhance patients‘ quality of life throughout the early course of ALS. As the disease progresses, patients need ventilation assistance (bilevel positive airway pressure - BiPAP) and invasive nutritional approach (nasoenteral tube or percutaneous endoscopic gastrostomy feeding) [63]. The first therapeutic step in PSP is identifying and prioritizing symptoms. Gait instability should be addressed with fall precautions, walkers and physiotherapy; visual disturbances may be alleviated with separate glasses for close and far distances or prism glasses; parkinsonism sometimes responds to levodopa in doses higher than used in Parkinson‘s disease. The management of dysphagia and dysarthria is similar to what was described to ALS [64]. Therapy for patients with low-grade astrocytomas, either well circumscribed benign (WHO grade 1) or diffusely infiltrating with only increased cellularity (WHO grade 2), is controversial. Complete resection may be limited to a select group of patients with small Neurological Diseases with Pharyngeal Dysfunction 17 unilateral tumors or tumors that do not involve critical brain structures. Immediate radiation therapy extends the time to recurrence, but there is no convincing evidence that early radiation therapy improves overall survival. The role of adjuvant chemotherapy remains under investigation. Anaplastic astrocytomas have mitoses (WHO grade 3), and radiation therapy has been shown to prolong survival, being a standard component of treatment. The benefit of adjuvant chemotherapy remains unconfirmed. However, chemotherapy benefits patients with anaplastic astrocytomas that recur after radiation; both nitrosoureas and temozolomide have shown efficacy. Glioblastoma multiforme (GBM) have evidence of endothelial proliferation and/or tumor necrosis (WHO grade 4), and radiation therapy plus concurrent temozolomide has recently become the standard treatment of patients with GBM. The treatment options for GBM recurrence must be carefully weighted given the needs of each patient, and palliative care need to be considered [65]. During the acute posttraumatic period, the need for surgical intervention is decided by two factors: the clinical status of the patient and CT scanning. A sizable epidural, subdural, or intracerebral blood clot that is causing a shift of central brain structures is an indication of immediate surgery. The presence of posttraumatic contusions, brain edema, and displacement of central structures calls for measures to monitor progression of these lesions and to control raised intracranial pressure. These measures are best carried out in an intensive care unit [1]. There is no specific treatment for the congenital pseudobulbar palsies. Alike other types of cerebral palsy, a multidisciplinary team with a wide range of expertise should manage these children. The response to conventional speech and language therapy is controversial and not proven, thus early alternative communication methods should be provided to support their cognitive and psychosocial development. Treatable complications, such as aspiration, malnutrition and gastro-esophageal reflux, should not be missed [66]. Currently, there is no cure for Kennedy‘s disease. Medical and physical therapy should be directed towards reduction of pain, muscle cramps and other symptoms [38]. As syringobulbia is usually associated with Arnold-Chiari malformation, their treatment is basically the same: posterior fossa craniectomy (suboccipital decompression), duraplasty (dura enlargement with a patch created from synthetic material or tissue from the patient), upper cervical laminectomy, sometimes associated with a CSF shunt and/or autogenous bone grafts in selected cases [67]. Patients with suspected viral AFP require careful observation of swallowing function, vital capacity, pulse, and blood pressure in anticipation of respiratory and circulatory complications. Physical therapy and ortheses prevent contractures, ankylosis, foot drop and other deformities. Respiratory failure calls for the use of a positive-pressure respirator and, in most patients for a tracheostomy as well [1]. There is no proved antiviral therapy for AFP caused by enteroviruses or arboviruses. Application of high-dose corticosteroids or immunotherapeutic interventions has not been systematically studied in viral AFP, although anecdotal evidence has reported benefit in some patients [68]. Suspected cases of Guillain-Barré syndrome (GBS) and its variants should be monitored closely for any degree of respiratory failure (hypoxia, weak cough, aspiration, fast declining respiratory function) or dysautonomia (lability of heart rate and blood pressure). The former calls for immediate intubation, while the latter usually demands conservative measures with the occasional use of short-acting agents, except for second- and third-degree heart block that 18 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini may require temporary pacing. The only specific treatments for GBS that have proven effective are plasma exchange therapy (PE - two to four exchanges) and intravenous serum immune globulin (IVIG - 0,4g/kg/day for 5 days). Since the incidence of side effects with IVIG is lower than with PE, IVIG is now preferred as the first-line agent, if it is available [22]. First line treatment for CIDP is accepted as steroids, IVIG and PE. The cost benefits of these therapies in the short and long term remain a matter of debate; although IVIG is the most expensive option in the short term in 2008, it probably has the fewest short-term side effects and appears to have a favorable long-term risk profile [22]. The treatment of chronic leptomeningitis or pachymeningitis should be directed towards the etiological factor [1]: tuberculosis (rifampin, isoniazid, pyrazinamide, sometimes ethambutal or ethionamide, associated with corticosteroids in immunocompetent patients) [69], fungal (amphotericin B, sometimes combined with other antifungal agents), carcinomatosis (cranial radiotherapy combined with systemic and intrathecally chemotherapy), sarcoidosis (corticosteroids and/or cyclosporine), rheumatoid arthritis (the use of corticosteroids and immunosuppressants has not been shown to have any significant effect on this ominous condition) [50], syphilis (penicillin G 18 to 24 million units daily or 0,15 million units/kg/day for 10 to 14 days) [70,71]. If substantial mass effect is observed in patients with meningiomas, the treatment of choice is usually complete resection, which is often feasible over the posterior fossa. Under difficult circumstances, radiotherapy may be extremely useful for tumor control, including stereotactic radiosurgery for smaller lesions (<3-4 cm) and fractionated stereotactic radiotherapy for larger lesions or meningiomas near critical structures. No chemotherapy have reproducibly demonstrated antitumor efficacy for meningiomas [65]. Posterior fossa aneurysms are particularly difficult lesions due to the complex anatomy of the posterior fossa, the high eloquence of the neural contents, and the depth of the operative field. The surgical therapy with the clipping technique is used more often, but vessel ligation with or without bypassing procedures should be considered, especially in large and complex lesions. Endovascular treatment should be offered to patients whose medical condition precludes general anesthesia [24]. If the jugular foramen syndrome is caused by a glomus jugulare tumor, the treatment can be managed in three ways: careful serial observation with catecholamine blockage in some cases, as it is often diagnosed in elderly patients; radiation treatment is advised as the sole treatment modality for elderly and infirm patients who are symptomatic, especially those with extensive and growing tumors; the surgical therapy is the treatment of choice and its approach depends on the involvement of the carotid canal (radical resection) and intracranial extension (combined otological and neurosurgical operation is required) [72,73]. Although the mainstay of treatment for carotid body tumors is surgical excision with or without prior intravascular embolization, small tumors in elderly patients with high operative risk can be managed by observation only. Differently from glomus jugulare tumors, these tumors are historically considered resistant to radiotherapy, though recent studies raised some controversy about this issue [74]. Neurinomas of the 9th, 10th and 11th cranial nerves are grouped together as jugular foramen neurinomas because clinical and even operative identification of the exact nerve is often impossible. The preferred treatment in most symptomatic cases has been surgical excision [75,76]. Skull-base metastases appear late in Neurological Diseases with Pharyngeal Dysfunction 19 the course of the primary neoplasm, carrying an overall poor prognosis. In addition to symptomatic treatments with steroids and analgesics, specific treatments usually include: radiotherapy; sometimes chemotherapy or hormonotherapy, according to the sensitivity of the primary tumor; and rarely surgical removal [77]. At the present time, there are no treatment guidelines for internal jugular vein thrombosis (IJVT) and careful decisions should be taken. Although the risk of pulmonary embolism is actually unknown and many patients with undiagnosed IJVT do well, the use of anticoagulant therapy should be considered as a recent retrospective study showed pulmonary embolism rates of 0,5% for IJVT alone and 2,4% for combined IJVT and subclavian/axillary vein thrombosis [78]. Independently of the presence of infection, an indwelling catheter should be removed from the internal jugular vein whenever possible. In the case of infected IJVT associated with central venous catheters, the promptly institution of vancomycin as soon as blood cultures are obtained is highly recommended and can be later modified according to culture data [79]. In all other cases of infected IJVT, the antibiotic therapy should be directed against anaerobic organisms as well, and a prolonged duration of therapy is required. Surgical therapy is reserved for cases associated with deep neck infections that require drainage and debridement; and extremely rare occasions of persistent intraluminal abscesses requiring resection of the internal jugular vein [80]. There are no reports demonstrating the use of a superior vena cava filter (Greenfield) for isolated IJVT. Most cases of basal skull fractures are considered stable fractures, so they are managed using conservative methods satisfactorily. Neurosurgical treatment of stable occipital condyle fractures (OCF) involves neck stabilization, which is achieved with a hard collar (Philadelphia) or halo traction. Unstable OCF requires early surgical intervention with atlantoaxial arthrodesis. Delayed surgical therapy is indicated for persistent CSF leakage after a skull base fracture. Sometimes, neurological decompression of a bony fragment is necessary, but its surgical management is particularly difficult [55]. Generally, the core of successful therapy for parotid tumors is adequate resection incorporating a surrounding cuff of normal tissue followed, when appropriate, by radiation therapy. The relatively high incidence of local recurrences justifies the performance of a total parotidectomy in most cases, and neck dissection should be carried out if nodes are present or if the tumor has an elevated tendency to lymphatic spread [81]. There is no general consensus for the management of internal carotid artery dissection (ICAD), but medical, endovascular, and surgical options may depend on the characteristics of the injury and comorbidities. Anticoagulation with intravenous heparin followed by warfarin has generally been accepted as medical management to prevent thromboembolic complications, while antiplatelet therapy has been used when anticoagulant therapy is contraindicated [82]. However, a Cochrane review found no randomized trials testing these drugs in people with ICAD and demonstrated that there was no evidence that anticoagulants were better than aspirin [83]. Expanding or symptomatic dissecting aneurysms and/or refractoriness to medical therapy may be indications for angioplasty and stent placement [84]. Myasthenia gravis (MG) is one of the most treatable neurological disorders. Acetylcholine esterase (AChE) inhibitors are the mainstay of symptomatic treatment of MG, raising the concentration of the ACh at the neuromuscular junction and increasing the chance of activating the muscle AChR. Pyridostigmine is the preferred AChE in clinical use and 20 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini patients with AChR antibodies respond well to treatment, while patients with MuSK antibodies usually do not [85]. Most patients with generalized MG require immunomodulating therapy, including corticosteroids, immunosuppressants (azathioprine, cyclosporine, cyclophosphamide), IVIG, and PE. Limited evidence from randomized controlled trials suggests that: corticosteroids offer significant short-term benefit compared with placebo; MG improved significantly with either cyclosporine (alone or in combination with corticosteroids) or cyclophosphamide (in combination with corticosteroids) compared with placebo. On the other hand, these trials demonstrated no difference in efficacy between: corticosteroids and either azathioprine or IVIG for moderate MG exacerbations; and IVIG (1g/kg/day for one or two days) and PE for severe MG exacerbations [86-88]. Thymectomy is an important treatment option in early-onset (onset ≤ 40 years) and thymoma-induced MG with AChR antibodies, whereas evidence for a favorable response to thymectomy in both MuSK and seronegative MG is limited [89,90]. Respiratory insufficiency associated with MG may be either a myasthenic crisis (normal pupils and good motor response to AChE) or a cholinergic crisis (miosis and respond to AChE with salivation, lacrimation, urination, defecation, gastrointestinal upset, and emesis, also known as the SLUDGE syndrome). Although BiPAP can prevent intubation in patients with myasthenic crisis, the presence of hypercapnia at the time of the BiPAP initiation predicts failure and the need to proceed to endotracheal intubation with a nondepolarizing paralytic agent [91]. In the case of the Lambert-Eaton myasthenic syndrome (LEMS), initial treatment should be aimed at the underlying malignancy because weakness frequently improves with effective cancer therapy, sometimes requiring no further treatment. If no neoplasm could be found, symptomatic treatment and immunotherapy are promptly justified. Limited evidence from randomized controlled trials showed that either 3,4-diaminopyridine (potassium channel blocker that increases action potential duration at the motor nerve terminal which leads to increased calcium influx and greater ACh release) or IVIG improved muscle strength scores and compound muscle action potential in patients with LEMS. Other possible treatments similar to MG, such as corticosteroids, immunosuppressive agents and PE, have not been tested in randomized controlled trials [92]. After the suspicion of foodborne botulism, local and state public health officials should be immediately contacted to provide trivalent botulism antitoxin and to assure the source is identified and controlled, avoiding a larger outbreak. After skin testing for sensitivity, administration of a single vial of the botulism antitoxin IV is sufficient to arrest the progression of the paralysis. Careful monitoring of respiratory vital capacity and intensive care should be performed for the duration of the prolonged paralytic illness, time required for the regeneration of presynaptic axons and formation of new synapses [36]. Since idiopathic inflammatory myositis is relatively uncommon, randomized clinical trials are scarce and their optimal treatment is decided on general clinical consensus with the balance of the little evidence available. Corticosteroids are accepted as the first-line effective therapy for both polymyositis and dermatomyositis. If treatment with corticosteroids is not successful, other types of therapy are considered, most commonly combination therapy with azathioprine or IVIG therapy. In the case of severe extramuscular disease, stronger immunosuppressive treatment regimens are recommended, whilst alternative therapies are reserved for refractory disease. Sporadic inclusion body myositis (IBM) is often resistant to Neurological Diseases with Pharyngeal Dysfunction 21 therapy, but a treatment trial with monthly IVIG appears reasonable [93]. The treatment of both myotonic and oculopharyngeal muscular dystrophies are mostly symptomatic. The myotonic phenomenon can be relieved with either phenytoin or carbamazepine [94].

2.3 Pharyngeal Movement Disorders

2.3.1 Etiology The etiology of pharyngeal movement disorders includes palatal tremor, pharyngeal dystonia and cricopharyngeal spasm. Palatal myoclonus was reclassified among the tremors to acknowledge the continuous, rhythmic nature of the jerks of the soft palate [95]. Pharyngeal dystonia is often associated with other focal dystonias like laryngeal dystonia, which is also known as spasmodic dysphonia (SD) [96], but it may be found in isolation [97]. Cricopharyngeal spasm can be the cause of cricopharyngeal achalasia and dysphagia, thus these terms are sometimes used synonymously and included in cricopharyngeal dysfunction [98].

2.3.2 Pathophysiology Palatal tremor is divided into two distinct forms: symptomatic palatal tremor (SPT) and essential palatal tremor (EPT) [99]. SPT occurs almost exclusively in adults and it is often the result of a neurological lesion in the triangle of Guillain and Mollaret (dentatorubral-olivary connections) such as brainstem stroke, trauma, multiple sclerosis or degenerative disease. Such lesion is believed to cause autonomous oscillations of the inferior olive with its hypertrophy and degeneration, which causes rhythmic contractions of the levator veli palatini muscle. On the other hand, EPT mainly occurs in children, and the pathophysiology of the rhythmic contractions of the tensor veli palatini muscle is unknown [99]. A rare subgroup is characterized by a progressive condition with progressive ataxia and palatal tremor [100]. Pharyngeal dystonia, henceforth described under the term laryngopharyngeal dystonia (LPD) due to their usual association, can be divided in primary or secondary types. In primary cases, dystonia is the only clinical sign (except for eventual associated tremor) and there is no neuronal degeneration or an acquired cause. In secondary cases, dystonia is associated with hereditary neurological syndromes, degenerative parkinsonian disorders (Parkinson disease will be addressed in ―Dysphagia and aspiration‖), and acquired or exogenous causes. Although primary dystonias are most commonly due to mutations in the DYT1 gene encoding the protein torsinA, LPD is a prominent sign of mutations in DYT4, DYT6 and DYT13 genes [101]. Among the secondary dystonias, acute [102] and tardive [97] dystonias due to dopamine receptor blockers are noteworthy. There are two main types of SD: the adductor SD is caused by irregular hyperadduction of the vocal cords; and the abductor SD, which is characterized by the contraction of the posterior cricoarytenoid muscles during the action of speaking, resulting in inappropriate abduction of the vocal cords [103-104]. Other authors include a mixed type, and a fourth type of laryngeal dystonia that is triggered by inhalation, which causes breathing disorders and does not affect phonation [96]. Cricopharyngeal achalasia may be primary or secondary. Primary cricopharyngeal achalasia implies that the idiopathic abnormality leading to the persistent spasm or failure of 22 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini relaxation of the cricopharyngeus muscle is confined to the muscle, with no other underlying neurological or systemic cause. The cricopharyngeal spasm may be secondary to other neurological disorders such as poliomyelitis, oculopharyngeal muscular dystrophy, stroke, and amyotrophic lateral sclerosis [98].

2.3.3 Diagnosis Palatal tremor is clinically visible as a rhythmic movement of the edge of the palate. SPT does not disappear with sleep, barbiturate anesthesia, or deep coma, but it does not cause discomfort for patients, except when associated with pendular nystagmus and oscillopsia, where objects annoyingly seem to oscillate. In addition, many patients present a unilateral or bilateral cerebellar syndrome. MRI can demonstrate the hypertrophic degeneration of inferior olive associated with brainstem or cerebellar dysfunction of SPT. [99]. In contrast, EPT lacks CNS lesion or olivary pseudohypertrophy and patients often complain of a rhythmic ear click [99,105]. Primary SD is characterized by gradual onset in the forth and fifth decades of life with marked female predominance. After one or two years of progression, the disease tends to stabilize and become chronic. Sometimes, patients have a voice tremor that may precede the onset of SD by several years. Unfortunately, many patients are referred to psychological evaluation because SD is worsened by emotional stress and relieved by tranquilizers, while correct diagnosis is not made when they look for treatment [96,103]. Patients with adductor SD exhibit a choked, strained and strangled voice with abrupt initiation and termination of vocalization, resulting in short breaks of phonation. The abductor SD is much less common, consisting of prolonged vocal fold openings producing breathy and whispering voice and phonatory pauses extending into vowels [103-104]. Sometimes, acute LPD due to dopamine receptor blockage may cause excessive and uncontrolled closing of the vocal cords, resulting in a medical emergency that requires invasive respiratory support [102]. Occasionally, drug- induced tardive LPD result in prolonged dysphagia with no signs of dysarthria or dysphonia [97]. Correct diagnosis of LPD demands neurological, laryngological and voice assessment, but the gold standard of SD evaluation is fiberoptic endoscopic laryngoscopy [96]. Cricopharyngeal spasm can lead to severe dysphagia and most patients primarily experience food sticking or catching in the lower third of the neck. Although the true incidence of cervical dysphagia caused by cricopharyngeal dysfunction is unknown, the literature reports cricopharyngeal achalasia as the primary cause of or as a contributor to dysphagia in up to 25% of patients being evaluated for clinical symptoms of dysphagia. The best initial evaluation of suspected oropharyngeal dysphagia is a videofluoroscopic swallowing study, which can evaluate motility of the oropharynx and hypopharynx and provide double-contrast views that may identify structural abnormalities [98].

2.3.4 Treatment The treatment of patients with SPT is symptomatic. Pendular nystagmus and oscillopsia can be treated with memantine, gabapentin, clonazepam, or trihexyphenidyl, but an adequate response is not guaranteed [106]. In EPT patients, the major problem is the ear click. Several treatments for EPT have been tried with inconclusive results and include: clonazepam [107], sumatriptan [108], valproate, flunarizine, and piracetam [109]. Currently the most effective Neurological Diseases with Pharyngeal Dysfunction 23 therapy is the treatment of the click by injection of botulinum toxin (BTX) into the tensor veli palatini muscle [110]. Until the introduction of BTX, the therapy for primary SD had been disappointing. Several studies have established the efficacy and safety of BTX in the treatment of focal dystonias, including LPD, and this approach is the treatment of choice for SD. Before the BTX injection, the diagnosis must be confirmed and documented by voice and video recordings [111-112]. After the diagnosis of a secondary LPD, the cause should be treated or removed whenever possible. The treatment of choice for cricopharyngeal spasm used to be cricopharyngeal myotomy. Recently, botulinum toxin injection may be preferred over surgery because of lower risk, lower cost and demonstrable effectiveness of the procedure [113-114].

3. Disorders of Somatic Sensation

The disorders of pharyngeal somatic sensation can be divided in pharyngeal anesthesia and pharyngeal neuropathic pain. Analogous to disorders of motility, they may result from lesions in various parts of the nervous system [1,14]:

The glossopharyngeal nerve transports sensation from the pharynx, tonsil, and posterior third of the tongue via its pharyngeal, tonsillar, and lingual branches; the pharyngeal and superior laryngeal branches of the vagus nerve help to form the sensory pharyngeal plexus. The spinal trigeminal tract is located at the lateral medullary tegmentum and it receives the afferent fibers of the pharyngeal plexus. These fibers descend to various levels and then synapse in the adjacent nucleus of the spinal trigeminal tract. The trigeminothalamic tract, or trigeminal lemniscus, is formed by the crossed fibers from the contralateral nucleus of the spinal trigeminal tract. It ascends to the ventral posterior medial thalamic nucleus alongside the spinothalamic tract and the medial lemniscus at the upper brainstem tegmentum. The thalamoparietal or sensory radiations project to the sensory cortex in the postcentral gyrus, where the pharyngeal sensation occupies a small area in the lower third.

3.1 Pharyngeal Anesthesia

3.1.1 Etiology The etiology of pharyngeal anesthesia may be classified according to the localization of the disease process and the resulting syndrome [1,14]:

The glossopharyngeal nerve is usually affected in retropharyngeal, retroparotid or posterior lateral condylar spaces lesions, or in jugular foramen or skull base lesions. Isolated glossopharyngeal palsy is a rarity [115] and it has almost always been seen 24 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini

in conjunction with sympathetic and other cranial nerves palsies, as described previously in ―Pharyngeal paralysis‖. Lesions of the lateral medullary tegmentum, where the spinal trigeminal tract and nucleus are located, may involve the nucleus ambiguus as well, whose lesions have been described in ―Pharyngeal paralysis‖. Lesions of the trigeminothalamic tract are often due to vascular (upper brainstem stroke), demyelinating (multiple sclerosis), and neoplastic diseases (astrocytomas), the latter two have been described in ―Pharyngeal paralysis‖; while thalamic lesions are usually due to similar vascular and neoplastic diseases. Lesions of the thalamoparietal radiations are often due to vascular (lobar stroke), demyelinating (multiple sclerosis), neoplastic (astrocytomas), or traumatic diseases (craniocerebral trauma), the latter three have been described in ―Pharyngeal paralysis‖; while primary sensory cortex lesions are usually due to similar vascular, neoplastic (including meningiomas), or traumatic diseases.

3.1.2 Pathophysiology Atherosclerotic disease of small penetrating arteries, a frequent accompaniment of diabetes and chronic hypertension, is the common cause of infarction in the territory of:

The perforators and circumflex arteries from the basilar artery and its main branches, affecting the trigeminothalamic tract at the dorsal and lateral tegmentum of the upper brainstem [116-118]; The thalamogeniculate and posterior choroidal arteries, branches from the posterior cerebral arteries, affecting the ventral posterior medial thalamic nucleus [119]; The perforating medullary branches of the pial or superficial system of the middle cerebral artery, affecting the thalamoparietal radiations and primary sensory cortex [119].

These arterial territories may be the site of spontaneous intracerebral hemorrhage, a complication of arterial hypertension, intracranial vascular malformations, cerebral amyloid angiopathy, and other etiologies [119].

3.1.3 Diagnosis The clinical diagnosis of pharyngeal anesthesia is based on clinical examination, followed by etiological diagnosis. The gag reflex, and pain and touch sensation of the pharynx, tonsillar region and soft palate can be examined with a tongue blade, applicator stick, or similar object. At this time, the response on each side is compared. In common clinical practice, bedside testing of taste on the posterior third of the tongue is difficult and seldom attempted [14]. Rostral lesions of the dorsal pons result in the Raymond-Cestan syndrome that is characterized by ipsilateral cerebellar ataxia with a rubral tremor; contralateral hypesthesia of face and extremities; and there may be contralateral hemiparesis or paralysis of conjugate gaze toward the side of the lesion [116-117]. Lateral pontine lesions, especially those affecting the brachium pontis, result in the Marie-Foix syndrome that includes ipsilateral Neurological Diseases with Pharyngeal Dysfunction 25 cerebellar ataxia; contralateral hemiparesis; and variable contralateral hypesthesia for pain and temperature, sometimes involving the face [118]. Lateral mesencephalic lesions are characterized by contralateral hemiparesis; contralateral hypesthesia for pain and temperature; Horner‘s syndrome; and rarely ipsilateral or contralateral hearing loss [116]. Lesions at the thalamogeniculate arteries territory may result in the thalamic syndrome of Dejerine-Roussy that includes contralateral hemianesthesia; paroxysmal pain in the involved side (thalamic pain); hemiataxia and dysequilibrium (thalamic astasia); transient contralateral hemiparesis; and choreoathetoid movements and/or athetoid posture (thalamic hand). Lesions at the posterior choroidal arteries territory may result in hemisensory loss with mild hemiparesis; homonymous quadrantanopsia; decreased optokinetic nystagmus when moving the drum to the side of the lesion; and transcortical aphasia [119]. Lesions of the thalamoparietal radiations and postcentral gyrus result in contralateral sensory loss, which is more intense for touch than it is for pain; and contralateral paresthesias and pain, less often than thalamic lesions [119]. Most of the vascular lesions can be seen with a cranial CT, but brainstem lesions are reliably diagnosed with a cranial MRI. Sometimes, other additional exams are necessary to determine the exact etiology of the vascular lesion, such as an echocardiogram and an angiographic study [1].

3.1.4 Treatment The overall treatment of stroke was described in ―Pharyngeal paralysis‖. However, it is important to remember that recognition of acute stroke signs and symptoms should be followed by activation of the emergency medical services, and that hypotension and excessive blood pressure reduction must be avoided in the acute phase [56]. It is also essential not to forget that early physical therapy and rehabilitation is beneficial for most patients, and that preventive measures for atherothrombotic disease must be taken whenever possible [1].

3.2 Pharyngeal Neuropathic Pain

3.2.1 Etiology The causes of pharyngeal neuropathic pain include glossopharyngeal neuralgia, superior laryngeal neuralgia, glossopharyngeal zoster, and laryngopharyngeal dysesthesia. According to the second edition of the International Classification of Headache Disorders (ICHD-II), the Eagle syndrome is not recognized as a distinct headache disorder yet and it will be described with glossopharyngeal neuralgia [120].

3.2.2 Pathophysiology Alike trigeminal neuralgia, glossopharyngeal neuralgia is divided in classical and symptomatic forms [120]. The classical form is caused by demyelination of the root entry zone of the glossopharyngeal nerve in the medulla secondary to neurovascular compression. Tumors, multiple sclerosis, carotid aneurysm, tonsillar abscess, occipital-cervical malformation, Paget‘s disease, Sjogren‘s syndrome, and an elongated styloid process and/or a calcified stylohyoid ligament (Eagle syndrome) may cause the symptomatic form [121,122]. 26 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini

In both forms, it is suggested that demyelination enables cross-talk and ephaptic transmission, leading to hyperexcitability of the glossopharyngeal nerve. The repeated stimulation of wide dynamic range neurons in the spinal trigeminal tract and nucleus is supposed to produce a progressive facilitation of excitability [121]. Superior laryngeal neuralgia may share similar mechanisms because compression of the nerve by the superior thyroid artery and/or vein can cause the syndrome. Viral infections may originate this neuralgia by direct infection or inflammation of the nerve or by a nonspecific inflammatory response that secondarily involves the nerve. Superior laryngeal neuralgia may be due to lateral pharyngeal diverticulum and can also develop after microsurgery, tonsillectomy, or trauma [122]. Like all other herpesviruses, varicella-zoster virus (VZV) establishes latent infection following varicella. Decline or suppression of VZV-specific cellular immunity is supposed to be the most important factor to the development of herpes zoster. Replication of VZV in the cranial sensory ganglion results in intense inflammation, neuronal destruction, and focal hemorrhage. Transmission of virus from the ganglion down the sensory nerve to the epithelial cells produces acute inflammation of the nerve and ballooning degeneration, acantholysis, multinucleated giant cells with eosinophilic intranuclear inclusion bodies among infected epithelial cells [18]. It is speculated that pain in herpes zoster results from such widespread neuronal inflammation [123]. Laryngopharyngeal dysesthesia may be a result of acute sensory neuropathy usually induced by oxaliplatin infusion, a third generation platinum derivative currently used in the treatment of colorectal cancer. It is suggested that oxaliplatin acts on specific sodium channels isoforms, which are present in isolectin B4 positive nociceptive neurons, to produce oxidative stress-dependent hyperalgesia [124]. Oxaliplatin induces laryngopharyngeal dysesthesia in about 2% of patients [125,126].

3.2.3 Diagnosis Glossopharyngeal neuralgia diagnostic criteria include [120]:

Paroxysmal attacks of facial pain lasting from a fraction of a second to 2 minutes and fulfilling the next two criteria. Pain has all of the following characteristics: unilateral location; distribution within the posterior part of the tongue, tonsillar fossa, pharynx or beneath the angle of the lower jaw and/or in the ear; sharp, stabbing and severe; precipitated by swallowing, chewing, talking, coughing and/or yawning. Attacks are stereotyped in the individual patient.

If there is no clinically evident neurological deficit and other causes have been ruled out by history, physical examination and/or special investigation, the term classical glossopharyngeal neuralgia should be applied even though neurovascular compression may be discovered during its course. If a causative lesion has been demonstrated by special investigations and/or surgery, the term symptomatic glossopharyngeal neuralgia should be applied, and the persistence of aching pain between paroxysms and/or sensory impairment in the distribution of the glossopharyngeal nerve may be found in this case [120]. In addition, Neurological Diseases with Pharyngeal Dysfunction 27

Eagle syndrome includes pain with head rotation and palpation of the styloid process in the tonsillar fossa [127]. Superior laryngeal neuralgia diagnostic criteria include [120]:

Pain paroxysms lasting for seconds or minutes in the throat, submandibular region and/or under the ear and fulfilling the next two criteria. Paroxysms are triggered by swallowing, straining the voice or head turning. A trigger point is present on the lateral aspect of the throat overlying the hypothyroid membrane. The condition is relieved by local anesthetic block and cured by section of the superior laryngeal nerve.

In the authors‘ opinion, although the ICHD-II describes only one form of superior laryngeal neuralgia, the classification in classical and symptomatic forms might be applied in the same fashion as trigeminal and glossopharyngeal neuralgias. Reports of both forms in the literature reinforce our opinion [122]. Isolated glossopharyngeal zoster is rare [128]. Sometimes, the Ramsay Hunt syndrome (facial palsy with or without vestibuloauditory involvement due to herpes zoster) may be followed by glossopharyngeal nerve and/or vagus nerve palsies. Glossopharyngeal zoster with associated laryngeal paralysis, but without facial palsy, is relatively uncommon and the diagnosis in such cases is not always easy to make. Some authors have reported that herpetic eruptions in the pharynx and larynx disappear faster than those occurring in the skin [129]. For definite diagnosis of VZV infection, serological, immunological or histopathological confirmation is essential. Serial serum complement fixation test and enzyme immunoassay IgG and IgM for VZV may help diagnose VZV infection when they show increasing antibody levels or an initial high IgM value followed by its decrement and an IgG shift. If there is no antibody titer fluctuation, it appears important to detect the presence of the VZV DNA by PCR in saliva, blisters, CSF etc, before making a diagnosis [129]. Some authors used direct immunofluorescence technique with a monoclonal antibody for definite diagnosis [128]. Laryngopharyngeal dysesthesia is characterized by a sensation of discomfort or tightness in the back of the throat and shortness of breath without any objective evidence of respiratory distress. These symptoms begin within hours of oxaliplatin infusion and may be typically triggered by cold stimulation. Despite being frightening, this sensation is usually transient and lasts from a few seconds to a few hours [130].

3.2.4 Treatment The treatment of symptomatic glossopharyngeal and laryngeal neuralgias should be directed toward the etiologic factor, such as styloidectomy for Eagle syndrome [127]. When it is not readily possible or there is no evident cause, both medical and surgical treatments may be used to treat these neuralgias. Medications that have proved effective in cases of trigeminal neuralgia could be used and carbamazepine is a first choice treatment at the smallest possible pain-relieving dose. Surgery should be considered as a treatment option for patients refractory to medical therapy. Section of the affected nerve roots has been the most 28 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini employed treatment and is generally considered curative. If there is compression of nerve roots by tortuous or enlarged vessels, microvascular decompression may be employed. In cases of high operative risk, percutaneous thermal rhizotomy and gamma knife surgery should be considered [122,131]. In the case of VZV cranial nerve palsy, like glossopharyngeal zoster, early initiation of antiviral therapy with intravenous acyclovir 10mg/kg three times daily for 7 – 21 days is the key to successful control of VZV infection [128-129]. The reduction of the inflammatory edema, constriction and ischemia by administering steroids is regarded as a necessary adjuvant therapy by some authors [129] and unnecessary by others [132]. There is no specific treatment for laryngopharyngeal dysesthesia other than observation. Preventive measures consist of prophylactic use of antioxidants (vitamin C, glutathione, L- carnitine etc), prolonged oxaliplatin infusion, and avoidance of cold exposure [124,130].

4. Disorders of Swallowing

The disorders of swallowing consist of dysphagia and aspiration. They may result from disorders of motility and/or disorders of somatic sensation, and many of them were previously described in this chapter. However, swallowing is a complex process that requires the coordination of volitional and automatic movements [133], which might be impaired in situations diverse from pure motor and/or sensory alterations. The initial and largely volitional phase of swallowing is also known as the masticatory or preparatory phase, while the automatic or reflexive phase of swallowing is also called the transport phase [133-134]. Dysphagia and/or aspiration may occur as a result of impairment in any or both swallowing phases. The swallowing neural network is coordinated via both cortical and brainstem regions as described below:

The volitional swallowing control is a diffuse bilateral cerebral system that includes the cingulate cortex and the supplementary motor area (movement planning and initiation); the primary motor cortex and operculum (movement execution); portions of the basal ganglia and cerebellum (movement coordination); primary sensory cortex, insula and portions of the parietal lobe (sensory input and integration), and other areas to a lesser extent [135-137]. The automatic swallowing control is a central pattern generator located at the brainstem that includes the reticular formation and trigeminal nucleus (probably related to oral transport phase), and the nucleus tractus solitarius (possibly associated with pharyngeal and esophageal transport phase), which are connected with the pharynx via both sensory and motor pharyngeal plexuses [134,137].

Neurological Diseases with Pharyngeal Dysfunction 29

4.1 Dysphagia and Aspiration

4.1.1 Etiology As mentioned earlier, dysphagia and/or aspiration may result from some disorders of motility and/or disorders of somatic sensation that were formerly described. In addition, some progressive degenerative diseases, such as Alzheimer disease (AD) and Parkinson disease (PD) might cause disorders of swallowing.

4.1.2 Pathophysiology The pathophysiology of dysphagia and aspiration associated with disorders of motility and disorders of somatic sensation was already explained and it is caused by the disruption of the primary motor and/or sensory pathways that are responsible for the oral and pharyngeal regions. The combination of cortical neuronal loss and neurotransmitter deficits leads to the appearance of a dementia syndrome that may originate swallowing disorders when cortical areas related to the volitional swallowing control are affected. In AD, two major hypotheses have been postulated to explain the molecular mechanisms of disease: the degeneration of cholinergic neurons of the basal forebrain is sufficient to produce memory deficit; and the abnormal processing of the amyloid precursor protein causes production, aggregation, deposition and toxicity of its beta-amyloid derivative [138]. PD results from the degeneration of dopaminergic neuronal cells in the pars compacta of the substantia nigra, which disrupts basal ganglia circuits, inhibits the motor cortex and impairs swallowing coordination. The proposed mechanism for neuronal loss in PD includes a hyperactive negative regulation of synaptic vesicle priming fusion to the Golgi apparatus by the alpha-synuclein protein (ASP). It may be explained by an inappropriate high expression of ASP or a defective degradation of the same protein, both with the capability of ASP oligomerization in Lewy bodies and vesicle trapping [139].

4.1.3 Diagnosis Symptoms and signs of dysphagia are not able to identify all patients with aspiration and it is particularly true in neurologically impaired patients, which may have recurrent pneumonia. However, it is helpful when patients complain of swallowing problems like a gurgly voice during and after meals; coughing before, during or after swallowing; increased chest secretions; weight loss; and slow eating [140]. The evaluation of dysphagia in neurological disease begins with the assessment of the level of consciousness, attention, memory and communication functioning. This information affects the entire swallowing evaluation and sometimes predicts oral and pharyngeal swallowing disorders, when preoral alterations, such as attention deficit, impair the oral phase and, consequently, the pharyngeal phase [139]. The clinical bedside assessment includes an examination of oral structural integrity (mucosa, salivation, dentition), cranial nerve function (motor and sensory), and swallowing (various consistencies and volumes) [139,141]. Symptoms that suggest silent aspiration include dysphonia, dysarthria, abnormal volitional cough, abnormal gag reflex, cough on trial swallow, and voice change on trial swallow. The presence of any 2 of these clinical features 30 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini has the highest sensitivity to identify the risk of aspiration with 92% of accuracy, while the presence of 4 clinical predictors increased specificity [139]. Other symptoms of dysphagia are nasal regurgitation and repetitive swallows. It is not established whether pulse oximetry and cervical auscultation increase sensitivity and specificity during the swallowing test [139]. The blue dye test has been used to identify aspiration in patients with tracheostomy. Although it is helpful when blue-dyed food leak out of or around the tracheostomy tube after the swallows, false negative results occur and require additional tests [140]. The two primary instrumental tools used to evaluate oropharyngeal dysphagia are videofluoroscopic swallowing study (VFSS) and fiberoptic endoscopic evaluation of swallowing (FEES) [139]. Sometimes, the measurement of pressures in the pharynx during swallowing (manometry) needs to be combined with VFSS (manofluorography) to identify the presence and severity of a pressure disorder and which structures and movements are creating the pressures in the pharynx [140]. AD core diagnostic criterion is a gradual and progressive change in memory function reported by patients or informants over more than 6 months associated with objective evidence of significantly impaired episodic memory on testing. The diagnosis of probable AD requires one or more supportive features: presence of medial temporal lobe atrophy; abnormal CSF biomarker (low amyloid β1-42, increased tau or phospho-tau concentrations); reduced glucose metabolism in bilateral temporal parietal regions on positron emission tomography (PET); proven autosomal dominant mutation for AD within the immediate family. The definite diagnosis occurs when either a mutation for AD on chromosome 1, 14, or 21 is confirmed, or abundant senile plaques (amyloid β1-42) and neurofibrillary tangles (tau protein) are present in the neocortex, entorhinal cortex, hippocampus, and amygdala of a patient with probable AD. [142] Bradykinesia is an indispensable diagnostic criterion for PD and must be associated with other characteristic features, such as rigidity (usually with the cogwheel phenomenon), resting tremor (with a frequency of 4-6 Hz), asymmetric onset, and sometimes an unexplained postural instability. Other causes of parkinsonism must be excluded. In clinical practice, the pathological confirmation of the hallmark Lewy bodies on brain specimen is not necessary and a well-documented substantial and sustained response to levodopa or a dopamine agonist is often sufficient to support clinical diagnosis [143].

4.1.4 Treatment As aforementioned, current methods of rehabilitation of dysphagia include behavioral swallowing therapy, medical interventions, and surgical therapy. Most patients with disorders of swallowing due to neurological disease demand an attempt at aggressive rehabilitation and specific medical treatment whenever possible. Behavioral treatment approaches may be classified in compensatory, rehabilitative, or both, depending on the specificity of the therapy and how it is implemented. Compensatory strategies result in temporary immediate benefit and postural changes (chin tuck posture, head rotations), dietary modifications (thickened liquids) and increased volitional control exemplify such approach. Rehabilitative strategies result in permanent improvement in deglutition over time and Lee Silverman voice treatment (LSVT) in PD [139,144], expiratory muscle strength training, neuromuscular electrical stimulation, and head-raise, tongue-hold Neurological Diseases with Pharyngeal Dysfunction 31 and lingual resistance exercises illustrate rehabilitative tactics. Swallow maneuvers (Mendelsohn maneuver, supraglottic and effortful swallow), breath-hold exercise, and sensory enhancement techniques (bolus with strong sensory characteristics and thermal tactile stimulation) can be considered both compensatory and rehabilitative [139]. There are no medications to specifically improve the pharyngeal phase of swallowing so far. However, medical treatments for some neurological diseases may positively affect the swallowing function. It is particularly true for myasthenia gravis, where cholinesterase inhibitors might be timed with meals to provide optimal muscular performance, and for PD [139]. Botulinum toxin has been injected into a spastic cricopharyngeal muscle to treat upper esophageal sphincter (UES) dysfunction and into salivary glands to treat sialorrhea due to impaired ability to swallow the saliva [113-114,139]. UES dilatation, either with pneumatic dilators or through bougienage, may also be used to disrupt the cricopharyngeal muscle and treat UES dysfunction [139], mainly in muscular diseases like oculopharyngeal muscular dystrophy (OPMD) [145]. Surgical treatment with cricopharyngeal myotomy has been performed to alleviate oropharyngeal dysphagia due to progressive muscular diseases like OPMD. No patient within 6 months of a sudden-onset and non-progressive disease, such as stroke, should receive surgical treatment as many patients recover function during this period of time [139-140]. Patients with intractable aspiration may be considered for surgical intervention. Conservative surgical procedures improve closure of the airway at the glottis and include medialization thyroplasty for a definitive incompetent larynx and injection laryngoplasty with collagen or fat when a future function recovery is expected. In the most severe cases, aggressive surgical approach is sometimes necessary and a tracheostomy may be performed for neurological patients with chronic uncontrolled aspiration [139-140,146-147]. All efforts should be attempted to improve swallowing safety and efficiency. However, when the dysphagia is severe and nothing alleviates the problem at once, then non-oral feeding is warranted. The use of nasogastric (NG) tube in stroke patients with dysphagia is reasonable because about half of them will recover swallowing function within a week, except for cases of lateral medullary stroke where percutaneous endoscopic gastrostomy (PEG) should be considered [139]. In amyotrophic lateral sclerosis, the early placement of PEG is highly recommended to avoid surgical complications caused by decreased vital capacity [63]. The use of all means of enteral tube feeding, particularly PEG, for patients with AD and other dementias associated with dysphagia is controversial. Although they are used in a very large number of patients, there is insufficient data to suggest that they are beneficial in patients with advanced dementia [139;148]. The standard symptomatic treatment for AD includes cholinesterase inhibitors and the partial N-methyl-D-aspartate (NMDA) glutamate receptor antagonist memantine. According to a Cochrane Library review, three cholinesterase inhibitors are equally efficacious for mild to moderate AD: donepezil, rivastigmine and galantamine [149]. The symptomatic beneficial effect of memantine in moderate to severe AD is believed to be a result of decreased glutamate excitotoxicity. The use of donepezil in patients with severe AD is approved by the American drug agency, but it is not approved by many other drug agencies around the world yet [150]. In order to control the motor symptoms in early PD, including the swallowing function in some patients, medical therapy includes: levodopa, dopamine agonists (such as pramipexole, 32 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini ropinirole and rotigotine), and monoamine oxidase-B inhibitors (selegiline and rasagiline). Surgical treatment should be considered in patients with advanced levodopa-responsive PD and uncontrolled motor fluctuations and dyskinesias. Deep brain stimulation of the subthalamic nucleus dramatically improves most of levodopa complications and it is considered the second major breakthrough in the treatment of PD, after the discovery of levodopa [151].

5. Disorders of Speech Articulation

The disorders of speech articulation consist of dysarthria and anarthria. They may result from many disorders of motility that were formerly described in other sections of this chapter. Furthermore, speaking is a complex process that requires the coordination of bulbar and respiratory musculature that might be impaired in situations diverse from pure motor alterations. Speaking is usually divided in an initial motor preparative phase followed by the motor executive phase and dysarthria and anarthria may occur as a result of impairment in any or both phases. In addition, normal speech depends on adequate timing and coordination, which occurs during the entire speaking process and includes real-time auditory feedback and speech regulation [152-155]. The proposed speaking neural network is coordinated via cortical and brainstem regions as described below [152-155]:

The motor preparative phase begins with word retrieval and sentence preparation, primarily, at the supplementary motor area, dorsolateral prefrontal cortex, and anterior insula in the dominant cerebral hemisphere. The speech timing and coordination process initiates at the superior cerebellum, usually contralateral to the dominant cerebral hemisphere. The motor execution phase is the activation of upper and lower motor neurons, their associated neuromuscular junctions, and bulbar and respiratory muscles. The speech timing and coordination process continues, predominantly, at the sensorimotor cortex, basal ganglia, thalamus, and at the inferior cerebellum, usually contralateral to the dominant cerebral hemisphere.

5.1 Dysarthria and Anarthria

5.1.1 Etiology As aforementioned, dysarthria and anarthria may result from some disorders of motility that were formerly described. Alike disorders of swallowing, some progressive degenerative diseases, such as Alzheimer disease (AD) and Parkinson disease (PD) might cause disorders of speech articulation as well.

Neurological Diseases with Pharyngeal Dysfunction 33

5.1.2 Pathophysiology The pathophysiology of dysarthria and anarthria associated with disorders of motility was already explained and it is caused by the disruption of the primary motor pathway that is responsible for the bulbar muscles. It may be called pure dysarthria or anarthria, where there is no abnormality of the cortical language functions. In this case, an educated dysarthric patient may be unable to speak a single intelligible word, but he has no difficulty in writing, reading and listening comprehension [1]. It is noteworthy that laryngeal muscles may also be affected, causing disorders of phonation, impaired production of vocal sounds in the larynx. Therefore, when the bulbar primary motor pathway is disrupted, vocal cords paralysis and consequent dysphonia and aphonia might accompany dysarthria and anarthria [1]. Defects in speech articulation may be divided into several subtypes [1,156]:

Neuromuscular (flaccid, atrophic, lower motor neuron) dysarthria is the result of disease of the motor unit, which means the lower motor neurons in the motor nuclei of the medulla and their peripheral extensions or cranial nerves, the neuromuscular junction, and the articulatory muscles. Pseudobulbar (spastic, non-atrophic, upper motor neuron) dysarthria is almost always the result of bilateral disease of the corticobulbar tracts. Rarely, unilateral upper motor neuron lesions, possibly due to variable availability of uncrossed motor projections among different individuals, cause mild to moderate dysarthria without the other symptoms of pseudobulbar palsy. Hypokinetic (rigid, festinating, parkinsonian) dysarthria is the result of extrapyramidal diseases associated with rigidity of muscles, sometimes a prominent aspect of speech in PD. Hyperkinetic (dyskinetic, choreic, myoclonic, dystonic) dysarthria is the result of extrapyramidal diseases associated with involuntary movements of bulbar and respiratory muscles, sometimes a highly characteristic speech in chorea and myoclonus. Ataxic (scanning, cerebellar) dysarthria is the result of damage to the cerebellum or its input and output pathways. Cortical (progressive) dysarthria or anarthria is the result of damage to Broca‘s area and surrounding dominant frontal operculum. It is typically characterized by difficulty in performing complex oral and facial movements, thus it seems to be more accurately labeled apraxia of speech [156], pure word mutism, aphemia, pure motor aphasia of Déjerine, mini-Broca‘s aphasia [1]. Another remarkable feature of this speech disorder is its temporality: speech is usually restored to normal when caused by a non-progressive lesion (stroke) or it often progresses to anarthria when caused by a degenerative lesion (AD).

5.1.3 Diagnosis The diagnosis of dysarthria depends on the analytic ear of the physician. Impairment of rapid syllable repetitions, also known as oral diadochokinesis, is considered a sensitive clinical sign of speech motor deficits [155,157]. The identification of different subtypes of dysarthria based on perceptual analysis alone is challenging. In clinical practice, dysarthria is 34 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini generally classified in the context of other disturbances found at the neurological examination or imaging as explained previously in this chapter. Neuromuscular dysarthria can begin with hypernasality, difficulty in uttering vibratory sounds, followed by slurring speech and difficulty pronouncing lingual and labial consonants. Pseudobulbar dysarthria often has a slow speech pattern with spasmodic dysarthrophonia, laughing and crying. Hypokinetic dysarthria usually has a monotonous voice, festinating speech, with low volume and inflection. Hyperkinetic dysarthria is characterized by a loud, harsh, improperly stressed or accented speech, which is abruptly interrupted by involuntary movements. In ataxic dysarthria, speech is generally slow with some explosive volume increments, monotonous, slurred, with the characteristic unnatural separation of syllables of words known as scanning. Cortical dysarthria is similar to unilateral upper motor neuron lesion and it is accompanied with oral and facial apraxia or other cortical impairments [1,156]. In addition to perceptual analysis, acoustic studies of speech can be informative as it affords quantitative analysis, a potential instrument for subsystem description and perceptual judgment correlation of intelligibility, quality, and subtype of dysarthria. Acoustic analyses include time (waveform or energy envelope of speech), frequency (Fast Fourier Transform or Linear Predictive Coding spectra), and time-frequency studies (spectrogram or waterfall spectral display) [157]. Chorea is defined as a syndrome characterized by a continuous flow of random, brief, involuntary muscle contractions. The syndrome can result from many diverse causes including infections, autoimmune disorders, genetic mutations, stroke, neoplasms, drugs, and metabolic disorders. The differential diagnosis of chorea relies on the presence of accompanying findings like cognitive decline in Huntington‘s disease (autosomal-dominant progressive degenerative disorder caused by a CAG trinucleotide repeat expansion in the gene encoding huntingtin on chromosome 4p16.3) and symptoms of rheumatic fever in Sydenham‘s chorea (neurological manifestation that may be related to molecular mimicry between streptococcal and CNS antigens) [158]. Ataxic dysarthria is usually part of the syndrome of cerebellar ataxia, which may include dysmetria, dysdiadochokinesis, nystagmus, and wide base gait with irregularity of steps and lateral veering. It can be the result of structural lesions (stroke, tumors), intoxication (alcohol, anticonvulsant drugs), metabolic disorders (hypothyroidism, celiac disease, vitamin deficiency), demyelinating disorders, paraneoplastic syndromes, Whipple disease, multiple system atrophy, hereditary cerebellar ataxias, etc [159].

5.1.4 Treatment Current methods of rehabilitation of dysarthria include behavioral therapy, medical interventions, and surgical therapy. Most patients with disorders of speech articulation due to neurological disease warrant a trial at aggressive rehabilitation and specific medical treatment whenever possible. Standard voice therapy aims to achieve a voice that is as normal, pleasant and effortless as possible. When standard voice therapies have been exhausted, augmentative alternative communication (AAC) modalities may be necessary. AAC options ranges from visual or gestural cues to computerized speakers. For neuromuscular dysarthria, early speech therapy Neurological Diseases with Pharyngeal Dysfunction 35 makes the voice stronger with greater prosodic range, but compensatory techniques with increased effort and loss of breath may be counterproductive in progressive diseases [160]. In cases of pseudobulbar dysarthria, early voice therapy teaches laryngeal massage, relaxation, stretch and flow phonation, with better respiratory support and control for speech [160]. For hypokinetic dysarthria, the Lee Silverman Voice Treatment (LSVT) has been proved the most beneficial. This therapy teaches the patient to self-cue himself to speak louder, better intoned and articulated [144,160]. Ataxic dysarthria may benefit of speech rate control methods like voluntary control, alphabet board, hand tapping and pacing board [141], and sometimes LSVT can be helpful [162]. There are no medications to specifically improve dysarthria yet. However, medical treatments for some neurological diseases may positively affect speech articulation. This is particularly true for myasthenia gravis and some patients with PD, in close similarity to swallowing disorders [139,144]. Voice amplification devices are useful in some cases of hypokinetic dysarthria, while palatal prosthetic augmentation may reduce hypernasality and improve speech in neuromuscular dysarthria and mixed dysarthria [160]. Surgical therapy includes palatal lift for patients with neuromuscular dysarthria and mixed dysarthria to reduce hypernasality and improve speech, associated or not with palatal augmentation prosthesis [160]. Alike swallowing disorders, other conservative surgical procedures improve closure of the airway at the glottis, serve as useful adjuncts to speech therapy, and include medialization thyroplasty for a definitive incompetent larynx and injection laryngoplasty with collagen or fat when a future function recovery is expected [160]. The cause of chorea should be treated or removed whenever possible like in drug- induced chorea, metabolic or endocrine chorea, and even in Sydenham‘s chorea with penicillin prophylaxis. In most cases, symptomatic treatment with antidopaminergic drugs is needed. Typical antipsychotics have bigger antichoreic activity than atypical ones, but with commonly unacceptable side effects. Valproic acid is widely used in the treatment of Sydenham‘s chorea [158]. Likewise, the cause of symptomatic cerebellar ataxia should be promptly treated or removed when it is due to intoxications, vitamin deficiencies, endocrine disorders, tumors, and other treatable causes. Therapeutic options for hereditary cerebellar ataxias are still very limited and it is often decided on a case-by-case basis [159].

6. Disorders of Breathing

Neurological diseases can cause a subgroup of sleep-related breathing disorders called obstructive sleep apnea (OSA). It may result from some disorders of motility, disorders of somatic sensation, and neurological degenerative disorders that were previously described in other sections of this chapter. The anatomy and neural control of the pharynx enable the upper airway (UA) to change shape and momentarily close for swallowing and speech. However, the collapsibility of the pharynx may impair the passage of air for breathing under certain circumstances [163]. In 36 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini order to understand how neurological diseases causes OSA, the knowledge of the UA reflex and its components is essential [164]:

Sensory component – In a normal respiratory cycle, inspiration generates a negative pressure and confers collapsibility to the UA. Sensory information in the UA includes mechanic receptors that provide encephalic feedback about pressure, airflow, temperature, and muscle tone. Cortical component – Central respiratory centers receive sensory inputs from the UA and an arousal is necessary to increase the tone of the UA, sometimes sensory input from chemic receptors also have a role in central arousal. Motor component – Pharyngeal dilators are activated, stiffen the soft tissues of the pharynx, and prevent UA collapse while promoting its patency.

The sensory, cortical, and motor components of the UA reflex are vulnerable to dysfunction and inadequate responsiveness to collapse, which is more prone to cause disorders of breathing during sleep [164]. Although purely anatomical factors also result in disorders of breathing, they will not be discussed here. Besides, the description of the whole breathing process is beyond the scope of this chapter.

6.1 Obstructive Sleep Apnea

6.1.1 Etiology Apart from obesity, male gender, and older age [163], some disorders of motility, disorders of somatic sensation, and neurological degenerative diseases that were formerly explained may lead to OSA.

6.1.2 Pathophysiology Neurological diseases may disrupt one or more components of the UA reflex to cause OSA as exemplified below:

Sensory dysfunction is probably important to various degrees in different phenotypes of OSA. The disorder of somatic sensation most related to OSA is UA hypo- or anesthesia, which was described in ―Pharyngeal anesthesia‖. Cortical arousal dysfunction might occur as a consequence of neurological degenerative diseases like Alzheimer disease, which was depicted in ―Dysphagia and aspiration‖. In addition, neurological degeneration theoretically affects sensory and motor pathways in the UA reflex as well. Motor dysfunction can affect muscles of respiration, such as the pharyngeal dilators, intercostals, or the diaphragm. Patients with disorders of motility described in ―Pharyngeal paralysis‖ are particularly susceptible to OSA.

Recently, Charcot-Marie-Tooth disease (CMT), the most common type of hereditary motor and sensory neuropathy, has been associated with OSA. CMT is caused by diverse mutations of genes encoding myelin or related proteins. OSA is suggested to be a sign of Neurological Diseases with Pharyngeal Dysfunction 37 pharyngeal neuropathy with abnormal pharyngeal sensory thresholds and muscle weakness, which result in increased collapsibility of the UA without evident diaphragmatic dysfunction [165].

6.1.3 Diagnosis The most common clinical manifestations of OSA are snoring and excessive daytime sleepiness, the latter can be subjectively assessed with the Epworth Sleepiness Scale. Other important features of OSA include sleep maintenance insomnia, restless sleep, parasomnias, gastroesophageal reflux, enuresis, erectile dysfunction, waking up gasping for air, or dry mouth [164]. According to a recent meta-analysis, the Berlin questionnaire was the most accurate questionnaire for predicting diagnosis of OSA, while the Kushida index was deemed to be an excellent clinical model for accurate diagnosis in repeated studies [166]. The most significant test elements associated with higher diagnostic accuracy were body mass index, history of hypertension, and nocturnal choking [166]. Overnight polysomnography is the gold standard for diagnosis of OSA. In adults, OSA is defined as ≥5 symptomatic or ≥15 asymptomatic episodes of cessation of breathing (apneas), partial airway obstruction (hypopneas), or respiratory effort-related arousals per hour, also known as the respiratory disturbance index (RDI) where each event last at least 10 seconds [167]. It is suggested that 5 ≤ RDI < 15, 15 ≤ RDI <30 and RDI ≥ 30 indicate mild, moderate and severe symptomatic OSA [168]. Children require at least one obstructive event commencing for at least two respiratory cycles per hour [169]. CMT type 1 accounts for more than two-thirds of CMT cases and is characterized by slowly progressive weakness of the distal muscles of the arms and legs, atrophy, sensory loss and foot deformities. ENMG shows a decrease in motor and sensory nerve conduction velocities and pathological examination demonstrates demyelination. Definite diagnosis is based on genetic testing [165].

6.1.4 Treatment Alike other pharyngeal dysfunctions, current treatment options for OSA include behavioral therapy, medical interventions and surgical therapy. All these treatments can be used in combination based on the severity of the OSA and patient preference, but specific medical treatment for the underlying neurological disease should be attempted whenever possible. Behavioral therapy includes weight loss in obese patients. Despite our unawareness of the physiological basis, it is clear that weight loss lead to improvement in OSA severity [163,170-172]. Alcohol and sedatives cause a reduction in the tonus of the pharyngeal dilators, thus avoidance of muscle relaxants should be included in behavioral interventions if feasible [170-171]. Sleeping in a more upright or lateral position may help reducing OSA severity in some patients [170-172]. These simple behavioral therapies are usually an adjunct to other treatments. Medical interventions include drug therapy, oral appliances and positive airway pressure devices. According to a Cochrane review, there is insufficient evidence to recommend the use of drug therapy in the treatment of OSA [173], but the American drug agency approved the use of wakefulness-promoting agents modafinil and armodafinil for the treatment of residual 38 Reinaldo Teixeira Ribeiro and Orlando Graziani Póvoas Barsottini excessive sleepiness as adjunctive therapies to other interventions for OSA [170]. The American Academy of Sleep Medicine currently recommends oral appliances for the treatment of mild to moderate OSA in patients who prefer them or do not respond to other therapies [174]. They include mandibular repositioning or advancement devices; tongue repositioning or retaining devices; soft palate lifters; and tongue trainers [170]. Positive airway pressure (PAP) devices are considered the standard treatment for OSA. Continuous PAP (CPAP) is the most used device to maintain the airways opened and it is effective in reducing symptoms of sleepiness and improving quality of life measures in patients with moderate and severe OSA [175-176]. Other devices like bilevel PAP (BPAP) and proportional PAP (PPAP) are used in certain circumstances. All PAP devices are applied by nasal mask or full-face mask [170]. A recent systematic review showed that there was no statistically significant difference between CPAP and dental devices subjective and objective sleepiness endpoints in patients with moderate OSA [176]. Surgical therapy in the treatment of OSA is a matter of recent controversy due to a paucity of high-level evidence on the comparative safety and effectiveness of UA surgery for treating OSA. In children, compliance with CPAP is difficult and tonsillectomy and adenoidectomy (T&A) is the treatment of choice [164]. However, a meta-analysis of current literature demonstrates that T&A often does not cure pediatric OSA. As T&A still offers significant improvements in the number of apneas and hypopneas per hour, it remains a valuable first-line treatment for most cases of pediatric OSA irrespective of the underlying cause [177]. In adults, available evidence suggests that UA surgery for OSA does not provide significant benefit over non-invasive options, but surgery should be offered only when less invasive treatments are ineffective, rejected or inappropriate [178-179]. The main surgical options include uvulopalatopharyngoplasty with septoplasty or tongue base reduction, nasal surgery, and maxillomandibular advancement [170]. Currently, there is no medical therapy capable of altering the progression of CMT. Hence, the treatment is focused on the management and prevention of physical disabilities related to CMT and on symptomatic treatment of neuropathic, musculoskeletal, cramping, and other pain.

7. Conclusion

Like other sciences, the knowledge about neurological diseases with pharyngeal dysfunction is under continuous and exponential growth. Nowadays, it is virtually impossible that a few professionals could perform all the complex actions associated with healthcare with the required efficiency. Neurological patients, in particular, often demand many physicians from different specialties and other professional caregivers to get the best assistance. The aim of this chapter was to review the available literature about the etiology, pathophysiology, diagnosis and treatment of the most common neurological diseases that can impair the main pharyngeal functions. Each section includes the neurological basis for multi- professional work. In order to expand his notion of specific aspects of a disease and its management, current scientific literature is offered to the reader in the references.

Neurological Diseases with Pharyngeal Dysfunction 39

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Chapter II

Pharyngeal Dysphagia

P. Claire Langdon and Kim M. Brookes Sir Charles Gairdner Hospital, Nedlands Western Australia

Abstract

Pharyngeal disease and/or dysfunction is responsible for many cases of dysphagia (difficulty swallowing). This can result in dehydration, malnutrition and life-threatening conditions such as aspiration pneumonia and choking. There can be a significant social cost in dysphagia, with patients who experience impairment in their ability to eat normally becoming isolated or embarrassed. Eating and swallowing problems can arise from a number of different aetiologies. These include neurological causes such as brainstem and cortical stroke, cranial nerve dysfunction, neoplasms including brain tumours and head and neck cancers, surgery, head injuries, congenital defects, myopathies, progressive neurological diseases such as Parkinson's Disease and Motor Neuron Disease (Lou Gehrig's Disease), trauma and burns. Dysphagia and its management is a highly specialised area which incorporates the skills of a multidisciplinary team in diagnosis and treatment. In recent years, the research into pharyngeal dysphagia has expanded knowledge of the area and has provided new and effective ways in which to alleviate eating and swallowing impairment. This chapter discusses causes of and current treatment approaches in managing and alleviating pharyngeal dysphagia.

Introduction

Swallowing is something we tend to take for granted. Within a day, the average person swallows around 2,400 times, with swallowing frequency changing from an average of 6 swallows per hour during sleep to 10 per hour during normal activity to around 300 per hour while eating (1). The body produces 1500ml-2000ml of saliva daily (2), which is swallowed without conscious thought. It is generally only when the normal sequence of swallowing goes wrong, or when something goes ‗the wrong way‘ that we become conscious of swallowing. 50 P. Claire Langdon and Kim M. Brookes

Yet it is an extremely complex and dynamic process, involving 5 pairs of cranial nerves and the coordinated action of 26 pairs of striated muscles (3-5) to transport food or fluid from the mouth to the stomach. Studies have provided evidence that the process of swallowing is governed by specialised neural networks in a finely-tuned partnership with respiration and speech (7). Neural control of swallowing is multidimensional. The brainstem contains the swallowing ‗Central Pattern Generator‘ – the first level of control. The second level of control incorporates the subcortical structures; basal ganglia, hypothalamus, amygdala and midbrain. The third level of control is represented by suprabulbar cortical swallowing centres (9). Normal eating and swallowing are extremely enjoyable and highly social functions which impact significantly on a person‘s quality of life. Imagine never being able to enjoy a meal, to celebrate a special occasion such as wedding or a birthday, or to enjoy a chilled glass of white wine on a summer evening. This is the reality for many people who experience dysphagia – difficulty eating and drinking. There are many etiologies that can cause dysphagia, and these may impact upon any of the phases of swallowing. This chapter will concentrate mainly on impairments that affect the incredibly complex pharyngeal phase of swallowing, but will touch upon some of the causes of both oral stage and esophageal stage impairments.

What Is Normal Swallowing?

Normal swallowing is generally divided into four stages for convenience of description, however, the normal swallow is a fast, continuous sequence of coordinated muscle movements and there is some overlap between the phases. They are briefly described below.

Oral Preparatory Stage (Voluntary Control)

The oral preparatory stage of swallow incorporates prior knowledge of feeding and swallowing, environmental, visual and olfactory cues. Food enters the oral cavity. The lips seal, the tongue accepts the food bolus and it is chewed. Taste buds are activated and information about the food is transmitted to the brainstem and cortex. This stage is under voluntary control: for example, if a cake has been baked with salt instead of sugar, it will be ejected from the mouth once this is tasted.

Oral Stage (Voluntary and Reflexive Control)

Food is chewed and mixed with saliva into a consistency that is optimal for swallowing. To achieve this, rotary jaw movements are tightly synchronised with movements of the tongue, cheeks, soft palate, jaw and hyoid bone (4). When the prepared food ‗bolus‘ is suitable for swallowing, it is centred on the tongue and propelled backwards by tongue movement through the anterior fauces to the oropharynx. Difficulties with the oral stage of Pharyngeal Dysphagia 51 the swallow can result in extended oral transit and retention of material in the oral cavity as residue, or as premature spillage of the bolus into the pharynx (3, 4). Pharyngeal Stage (Reflexive Control)

The pharynx consists of the

nasopharynx (above and behind the soft palate) and oropharynx (from the nasopharynx to the larynx)

Its role is to conduct air to and from the lungs and also move food and liquids from the mouth to the esophagus (8). The pharyngeal stage of the swallow has two primary objectives:

1. passage of food or liquids through the pharynx and upper esophageal sphincter (UES) to the esophagus and 2. airway protection – isolating the larynx and trachea from the pharynx during swallowing to prevent the bolus from entering the airway (4).

The pharyngeal swallow involves muscles of the soft palate, the tongue, pharynx, larynx and hyoid bone. During the normal swallow sequence, the soft palate elevates to seal off the nasopharynx and the bolus enters the pharynx due to posterior tongue propulsion. The bolus is propelled through the pharynx by the tongue base and by pharyngeal constriction. The pharyngeal constrictor muscles (superior, middle and inferior) overlap to form a sheath that extends from the base of skull to the esophagus. During swallowing, the lateral and posterior pharyngeal walls squeeze anteriorly and medially. The pharyngeal swallowing muscles are innervated by the trigeminal (V), facial (VII) glossopharyngeal (IX), vagal (X), spinal accessory (XI) and hypoglossal (XII) nerves (8). The swallowing sequence is shown in Figure 1. Eating, swallowing and breathing are tightly coordinated: breathing momentarily ceases during swallowing because of the physical closure of the airway and also because of neural suppression of respiration, mediated by the brainstem. Swallowing normally finishes with an exhalation of air. This serves to assist clearance of any material that may have entered the laryngeal vestibule during the swallow.

Esophageal Stage (Reflexive Control)

After the bolus enters the esophagus through the UES, peristalsis moves it downward and through the lower esophageal sphincter to the stomach. The peristaltic wave consists of an initial wave of relaxation to accommodate the bolus followed by a wave of contraction that propels it onward (4). The movement is a little like squeezing toothpaste through a tube.

52 P. Claire Langdon and Kim M. Brookes

What Is Dysphagia?

Dysphagia (Dis-fay-jar) comes from the Greek word ‗phagin‘ meaning to eat or swallow. Coupled with the suffix ‗dys-‗, the word means difficulty with eating or swallowing. Dysphagia is not a disease or condition in itself: rather, it is a sign or symptom relating to an underlying impairment or disorder. Problems can occur at any point of the ‗normal‘ swallow, from oral stage difficulties – for example, difficulty with chewing due to impaired dentition or absent saliva - to esophageal stage difficulties. This chapter will concentrate on the difficulties that may be experienced in the pharyngeal stage of swallowing. The main difficulties experienced by people with dysphagia are:

Reduced ability to maintain adequate nutrition and hydration Difficulties swallowing medications orally Aspiration: where food, fluid, saliva or secretions enter the airway. These may trigger coughing, or may be silently aspirated without triggering the protective cough response. If the aspirated material contains bacteria from the oral cavity, it may compromise the natural defences of the pulmonary system, and contribute to the development of a respiratory tract infection.

Figure 1. Normal Swallowing:

1. Food is chewed and mixed with saliva. This is shaped into a bolus by the tongue, and centred on the tongue prior to initiation of the swallow. The soft palate elevates to form a seal with the nasopharyx. 2. The tongue tip is pressed against the alveolar ridge, then the tongue base drops and the bolus is pushed into the pharynx. The vocal folds adduct and breathing is ceased momentarily. 3. The epiglottis deflects downward and the bolus enters the esophagus due to (a) tonic relaxation of the upper esophageal sphincter (b) hyolaryngeal traction opening the sphincter (c) pharyngeal squeeze. 4. The bolus is cleared into the esophagus by pharyngeal muscles exerting a stripping action. Pharyngeal Dysphagia 53

Why Prevent Aspiration?

Aspiration, the entry of food, fluids, saliva or secretions into the airway below the level of the vocal cords, is an event that occurs at some time in everyone‘s life. In a healthy system, occasional aspiration is not considered problematic, as respiratory defences exist that manage the aspirated material without pathological sequalae. These defences include respiratory mucous, cilia (fine hairlike substances that transport mucous out of the respiratory tract), alveolar macrophages and cough. It is usually only if the aspirated material is in particularly large quantities (significant aspiration of all materials), pathogenic in nature (such as large quantities of acidic vomit or bacteria-laden secretions) or the person has a particularly vulnerable immune system (such as elderly debilitated patients or those with high demands on their immune function) that respiratory tract infections develop (10). Unfortunately, many of the people who experience dysphagia are vulnerable to respiratory tract infections because their underlying etiology makes significant demands on their immune response, or because the quantities they aspirate are too large for their respiratory defences to cope with. The normal response to aspiration is a strong cough, which serves to expel material from the airway. In deep sleep, the cough reflex is partially suppressed. Studies have shown that normal subjects aspirate material during deep sleep (11). Subjects with poor cough strength and/or cough sensitivity may be more likely to develop respiratory complications associated with aspiration. These populations may include Parkinson‘s Disease patients, whose cough strength and sensitivity are diminished as part of the disease process (12). Naturally, pathological aspiration is to be prevented if possible. In addition to the obvious health issues, there are significant social implications for patients who cough and splutter at every mealtime or whenever they attempt to drink. A study that allowed access to water for stroke patients who were known to aspirate found that these patients chose to manage their dysphagia with a combination of both thickened fluids and water: the water for its propensity to quench thirst and the thickened fluids to allow the patients‘ to drink without aspirating (13).

Causes of Pharyngeal Dysphagia

Pharyngeal disorders and dysfunction can result in impairment to the initiation of swallowing, bolus propulsion, clearance of some or all of the bolus in the pharynx post swallow, nasal regurgitation and penetration or aspiration of material into the airway (4). Any, or a combination of impairments may mean that a person has difficulties in eating or drinking. These difficulties can lead to changes in behaviour; people modify their eating/drinking habits and may avoid foods or situations that they associate with difficulties. Extreme cases of dysphagia can lead to patients requiring alternative ways to maintain nutrition and hydration and people may require tube feeding to meet their needs. Apart from the added expense and practical difficulties associated with tube feeding, patients may miss the social aspects of eating and drinking. Sharing meals is a very important part of most peoples‘ lives, with food associated with cultural significance and major life events. Being 54 P. Claire Langdon and Kim M. Brookes excluded from participating in oral eating and drinking can be significantly detrimental for a person‘s quality of life.

Stroke

Stroke is the most common cause of acute oropharyngeal dysphagia, with incidence between 13% and 94%, depending on lesion location, severity of stroke and history of previous stroke (14-16). The part of the brain that is affected, conscious state and stroke severity are all factors that impact on a patients‘ ability to safely maintain nutrition and hydration following a stroke. Dysphagia is associated with an increased risk of aspiration. Pneumonia is up to seven times more likely to develop in stroke patients with confirmed aspiration (16-18). In acute stroke, the rate of chest infections is greatest in the first month post stroke (19-21), with many cases of dysphagia in patients with unilateral hemispheric stroke recovering spontaneously within the first two weeks (14, 17, 18). The neurology of swallowing includes cortical representation of swallowing and pharyngeal control in the motor area of the cortex, projections from the cortex to the brainstem via the corona radiata and internal capsule, brainstem central pattern generator and cranial nerve modulated output to the muscles of the head and neck (5). A lesion along any of these pathways can cause impairment to the swallowing mechanism and interruptions to the smooth modulation of the swallow process. In particular, cortical and brainstem strokes are associated with pharyngeal swallowing impairment. These are discussed in greater detail below.

Brainstem The swallowing ‗Central Pattern Generator‘ (CPG) produces the ‗automatic‘ part of the swallow where the bolus passes safely through the pharynx. The CPG integrates information about bolus size, density, temperature and texture into a coordinated motor program to allow successful swallowing to occur. It is located in the brainstem and involves the nucleus tractus solitarius (sensory) and nucleus ambiguus (motor). Interruption of the blood supply via ischaemic or haemorrhagic stroke can result in significant dysphagia. Brainstem strokes may leave the patient with a collection of symptoms collectively known as Wallenberg‘s or lateral medullary syndrome. The difficulties experienced by these patients include severe pharyngeal dysphagia characterised by difficulty initiating and coordinating a swallow. They may struggle to manage their own saliva, with enteral feeding necessary to sustain nutrition and hydration.

Cortical Cortical strokes, whether they are ischaemic or hemorrhagic, can cause significant problems with swallowing, with a very high incidence, particularly in the first month post stroke (22, 23). Pharyngeal phase problems include unilateral weakness and/or paralysis of pharyngeal muscles, delayed or absent swallow initiation, impaired airway protection and aspiration of food, fluid, saliva and secretions into the respiratory tract. This, coupled with Pharyngeal Dysphagia 55 impairment to the immune system caused by the neurological insult of the stroke, may result in respiratory tract infections in the acute period following a stroke (24). The severity of dysphagia in cortical strokes has recently been linked to hemispheric dominance of swallowing function. Swallowing has been shown to be bilaterally but asymmetrically represented in the motor cortex, with the dominant swallowing centre unrelated to hand preference (25). If a cortical stroke impacts upon the dominant swallowing centre, a significant dysphagia tends to occur. The non-dominant centre may subsume the functions of the dominant centre, with subsequent spontaneous recovery of swallowing function (26). Strokes in the non-dominant swallowing hemisphere tend to show a lower severity level and shorter duration of impairment. There have been several studies that show early therapeutic intervention can significantly reduce the impact of dysphagia in stroke patients and increase the chances of functional recovery (27-29). Indeed, principles of neural plasticity speculate that ‗use it or lose it‘ may be important (30), therefore maximising and maintaining residual function while working toward improvement of impaired swallowing should be considered in any dysphagia rehabilitation programme.

Other strokes Stroke may affect parts of the brain other than the cortex and brainstem. Impairment to the basal ganglia, particularly if it is caused by multiple strokes, may result in the same difficulties seen in Parkinson‘s Disease; that is, difficulty initiating and regulating movement. Cerebellar lesions may result in interruption to control of fine motor movement – an important component of swallowing – and in impairment to the connections between the cerebellar peduncles and the brainstem. These difficulties may result in dysphagic signs and symptoms for the stroke patient.

Neoplasms

Cancers of the head and neck are associated with significant dysphagia, either at the time the neoplasm develops, due to space constraints/compression of nerves and tissue or as a result of treatment interventions. Radiation therapy, in particular, is associated with dysphagia that sometimes manifests years after treatment, as the irradiated tissues gradually become more stiff and unyielding. Patients may experience loss of saliva production if salivary glands are exposed to radiation. Surgical interventions may also affect swallowing, due to removal or alteration of structures and, in some cases, sacrifice of nerves controlling muscles.

Brain tumours Brain tumours may be primary lesions or metastatic in origin and may cause significant dysphagia, depending on their location and size. Although many space occupying lesions are asymptomatic until they reach a size where they impact on neurological function, some small tumours can result in catastrophic impairment to eating and swallowing function if they impinge upon nerves or vital structures. For example, a posterior fossa or cerebellopontine 56 P. Claire Langdon and Kim M. Brookes angle tumour may compress cranial nerves involved with initiation and mediation of pharyngeal swallowing function. Tumours pressing on the brainstem may adversely affect the swallowing CPG while large invasive tumours such as glioblastoma multiforme may invade and destroy nerve tracts carrying information from the motor programming areas.

Head and neck cancers Management of patients with head and neck cancers affecting the oral cavity, pharynx or larynx may involve

1. Shrinking the tumour using radiotherapy, chemotherapy or a combination of radio- and chemotherapy prior to surgery or 2. By surgical removal of the tumour followed by radiotherapy, chemotherapy or a combination of the two.

The type and severity of dysphagia depends on the location and size of the original neoplasm, the structures involved and the medical interventions that are utilised (31). Patients who have resections of their posterior tongue or tongue base may experience increased pharyngeal residue and increased transit time, with the extent of resection impacting significantly on retained swallowing ability: patients with resections of greater than 25% of their tongue base may be unable to initiate a swallow and experience severe postsurgical aspiration (31). Those patients who have resections of the base of tongue experienced decreased tongue driving force, with incoordinated swallow and dyskinesia of the UES (41). Patients who undergo supraglottic laryngectomy are at high risk of aspiration due to removal of the structures involved in the protective mechanisms of the airway (31). Surgery that involves removal of the muscles that make up the suprahyoid complex (anterior belly of digastric, mylohyoid, geniohyoid and hyoglossus muscles) has been shown to cause significant dysphagia; while epiglottectomy does not increase penetration of material into the airway (40) due to the preservation of airway protective mechanisms. Patients who undergo hemilaryngectomy usually have a lower incidence of dysphagia, unless their surgery has involved removal of the arytenoid cartilage, with a rate of up to 91% of aspiration seen in these patients during swallowing due to impaired airway protection (32). Generally, patients who undergo a total laryngectomy experience reduced pharyngeal contraction and coordination but do not have difficulties with aspiration unless complications such as a postsurgical fistula occurs between the trachea and pharynx/esophagus with swallowed material leaking into the airway. Laryngectomy patients with a surgically created fistula between the trachea and esophagus for communication may develop a leak around or through the valve inserted into this fistula. This can allow aspiration of ingested material and requires urgent attention. Although radiotherapy provides important benefits, it has the unfortunate side effect of damaging normal tissue. This can result in mucositis, radiation necrosis, xerostomia and fibrosis. Swallowing impairment in the first months following treatment generally result from the surgical intervention while later dysfunction may develop as a result of radiation damage Pharyngeal Dysphagia 57 to tissue (32). Radiation treatment is one of the main predictors of poor swallow function after surgical removal of oral and oropharyngeal cancers (33).

Thyroid surgery Patients with thyroid diseases (e.g. lesions, goitres, cancers) often experience pharyngeal dysphagia, which is generally alleviated by surgery. However, as with all surgical interventions, thyroid surgery carries a risk, and patients who have experienced laryngeal nerve injuries during surgery report greater impairment on swallowing quality of life scales post surgery (39). The superior and recurrent laryngeal nerves are closely interrelated with both swallowing and airway protection. If these are stretched, transected or sacrificed during surgery then significant difficulties with swallowing may result. These can include impairment to hyolaryngeal excursion, difficulty initiating swallow, pharyngeal retention of material and impaired airway clearance due to unilateral vocal fold palsy.

Changes to Structural Integrity of the Pharynx

Anterior cervical fusion Anterior cervical fusion is carried out by orthopaedic surgeons and spinal neurosurgeons to alleviate pain and neurological symptoms (35). In some cases, patients may have dysphagia prior to their surgery due to compression of nerves. For other patients, surgery may cause pharyngeal dysphagia due to swelling or nerve involvement such as traction or severing. This may be transient or long lasting, and predispose patients to aspiration (36). Surgeons use either an anterior or posterior approach; evidence shows a decreased incidence of dysphagia with a posterior surgical approach, however this is associated with greater incidence of respiratory complications and infection rates (37). A retrospective review of 1015 anterior cervical discectomy and fusion cases reported incidence of dysphagia of 9.5%, with recurrent laryngeal nerve palsy occurring in 3.1% of cases (38). Rehabilitation in this group of patients may be difficult and prolonged, due to the need for fixation of the cervical spine during wound healing, and movement limitations from the surgery precluding dysphagia rehabilitation exercises such as head raising.

Osteophytes Osteophytes are bone spurs that form in response to degenerative changes in bone tissue. They are commonly seen in the elderly, and generally are asymptomatic. In some cases, cervical osteophytes are large enough to interfere with the pharyngeal swallow: either by preventing the normal downward tilt of the epiglottis during swallowing (44) or, more rarely, by combined obstruction and neurological dysfunction (45, 46). In a report of 9 patients with severe dysphagia caused by cervical osteophytes, surgical intervention resulted in resolution in all cases, with 7/9 cases experiencing immediate relief, while the remaining 2 cases resumed normal diet within months of their surgery (47).

Diffuse idiopathic skeletal hyperostosis (DISH) This is a condition where the anterior longitudinal ligament of the spinal column becomes ossified, and may be accompanied by osteophyte formation. It is a relatively rare 58 P. Claire Langdon and Kim M. Brookes condition, as DISH normally affects the thoracic spine, with only around 17% of patients experiencing dysphagic symptoms (42). DISH can cause dysphagia by giant osteophytes causing mechanical obstruction, impingement on the esophagus, pain and spasm, and/or secondary neurological dysfunction (43).

Cricopharyngeal dysfunction The Cricopharyngeus muscle of the pharynx is an important component of the UES. Cricopharyngeal dysfunction, where the muscle fails to relax to allow passage of a bolus, produces several symptoms of dysphagia. These may include choking or difficulty swallowing, nasopharyngeal reflux, globus sensation, aspiration and regurgitation and can manifest as a cricopharyngeal bar, spasm or incoordinated pharyngeal swallowing. Cricopharyngeal opening is due to hyolaryngeal excursion as well as relaxation of the normally tonically contracted cricopharyngeus muscle. Myotomy involves cutting the cricopharyngeus muscle using either an endoscopic or external approach and is indicated if patients have moderate to severe dysphagia with weight loss and/or pneumonia, if instrumental evaluation has shown poor cricopharyngeal relaxation is the cause, and if the patient can tolerate surgery (34). Other medical treatments used include dilations and botox injections into the cricopharyngeus to overcome the hypertonic muscle.

Zenker’s diverticulum Zenker‘s pharyngoesophageal diverticulum or ‗pouch‘ is an inpocketing of the posterior pharyngeal wall. Although the pathophysiology of the diverticulum is not completely clear, it appears that incomplete or poorly timed cricopharyngeal relaxation plays a role in its development (34). It is thought to be caused by the pressure of the food bolus against the tissues of the pharyngeal constrictor muscles, usually accompanied by poor opening of the upper oesophageal sphincter. With nowhere to go, the bolus is pressed tightly against the pharyngeal wall and causes an inpocketing of the posterior wall. Over time, this becomes larger and is generally diagnosed when patients present with the complaint of undigested material regurgitating some time after swallowing and halitosis. For unknown reasons, these diverticula tend to develop on the left side of the pharynx. They may be treated surgically or endoscopically.

Tracheostomy The introduction of an artificial airway to maintain respiratory integrity may impact on pharyngeal swallow function. In normal swallowing, an area of higher pressure exists in the trachea, while negative pressure gradients are maintained in the esophagus. If material enters the upper airway, this area of higher pressure facilitates the expulsion of the aspirated material. The presence of a tracheostomy interrupts these normal pressure gradients, making penetration of the laryngeal vestibule more likely, and impairs the patients‘ ability to clear this material. For this reason, many tracheostomy tubes used in the acute setting have an inflatable cuff, designed to minimise material from being aspirated into the respiratory tract. Tracheostomy tubes also impact upon pharyngeal swallow function by acting as a weight or anchor upon the normal superior-anterior movement of the hyolaryngeal complex when Pharyngeal Dysphagia 59 swallowing (48). This leads to decreased swallow efficiency, with reduced upper esophageal sphincter opening. This, in turn, promotes retention of material in the pharynx and increases the likelihood of this residue entering the upper respiratory tract post-swallow.

Head Injury and Trauma

Head injuries may result in a series of deficits including impaired cognition, decreased attention and concentration, visual disturbances, memory impairment, decreased insight into difficulties and motor control problems. The shearing and tearing forces associated with sudden acceleration/deceleration that accompanies many of these injuries results in diffuse axonal damage. Swallowing impairments of a motor nature include delayed initiation of swallowing and residue to the affected, hemiparetic side. Physical damage to the face and neck can cause fractures or puncture wounds. The most common swallowing impairment in brain-injured patients has been reported to be delayed or absent swallow (49). Cognitive impairments may result in patients ingesting material that is poorly prepared, thereby increasing choking risk. Impulsivity may mean that patients need to be monitored to prevent them attempting to swallow food that is too hot or at too fast a rate. Impaired insight into swallowing difficulties due to a patients‘ cognitive impairment may mean poor compliance with texture modified diets, thereby increasing the risk of aspiration in this population (50).

Progressive Neurological Dysfunction

Motor neurone disease/ALS/Lou gehrig’s disease Motor Neurone Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig‘s Disease, is a degenerative disease characterised by progressive muscle paralysis secondary to degeneration of motor neurones in the motor cortex, corticospinal tract and spinal cord. It is considered a relentless and rapidly progressive disease (51). Patients present with symptoms related to muscle weakness and wasting. Paralysis is progressive and generally leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset cases. Patients with bulbar onset MND usually present with dysarthria and dysphagia. The management is supportive, palliative, and multidisciplinary (52). The dysphagia associated with MND is related to muscle weakness, and presents as poor oral control, delayed pharyngeal initiation of swallow, poor UES relaxation due to lack of control of the cricopharyngeus muscle (53) and difficulties coordinating respiration and swallow function. Reduced respiratory capacity results in poor cough function, placing patients at risk of pulmonary obstruction by secretions or aspirated material (51). Saliva management is a significant problem for MND patients. Patients commonly report thick, stringy and tenacious secretions in the pharynx, or aspiration of thinner secretions. Both of these, coupled with poor cough function, result in feelings of airway compromise. 60 P. Claire Langdon and Kim M. Brookes

Parkinson’s Disease Parkinson‘s Disease is a relatively common (1% of the population aged 65 and over) disease of the basal ganglia (51). It is characterised by four cardinal features: tremor at rest, rigidity, akinesia and postural instability (54), and may be accompanied by dysphagia: one or all of the oral, pharyngeal and/or esophageal phases may be affected. The incidence of dysphagia has been reported to be as high as 77%, with delayed swallow, prolonged laryngeal excursion and extended esophageal transit the most frequent signs of swallowing impairment in this population (55). As Parkinson‘s Disease medication in tablet form needs to pass through the stomach to be absorbed, dysphagia management is a delicate balancing act that helps optimise care in this patient group.

Huntington’s disease Dysphagia of both oral and pharyngeal phases is common in Huntington‘s Disease patients. Difficulties controlling the passage of food or fluid to the mouth, cognitive impairment and decreased insight, impulsivity and chorea with uncontrolled movements contribute to oral phase difficulties. Difficulty sequencing breathing and swallowing, plus pharyngeal incoordination, leads to increased aspiration and choking risk and difficulties associated with swallowed air. Kagel and Leopold (1992) looked at 35 patients with Huntington‘s Disease and found swallow incoordination, repetitive swallows, prolonged laryngeal elevation, inability to cease respiration and belching frequently occurred, and could be managed with compensatory techniques. Maintaining safe oral intake for as long as possible and minimising choking risks are part of successful management of Huntington‘s Disease patients.

Myopathies

Myositis Swallowing dysfunction is commonly reported in patients with myositis (polymyositis and dermatomyositis), occurring more commonly in the acute inflammatory phase, and most frequently affecting UES function and esophageal motility (55). Most UES dysfunction in this population is treated with cricopharyngeal myotomy or Botox injections, with varying success reported (56).

Inclusion body myositis Inclusion body myositis has been described as one of the fastest growing incidences of degenerative disease in the aging population (57). While it is mostly diagnosed in people over the age of 65, it is increasingly diagnosed in patients aged less than 50 years (58). Compared to the other forms of inflammatory myopathies, inclusion body myositis has a very high incidence of pharyngeal phase dysphagia, mainly noted as pharyngeal residue secondary to impaired UES function. The mechanism behind this dysfunction has not been fully elucidated, though it is commonly managed as a hypertonic UES. Treatment involves artificial relaxation of the UES through Botox, dilatation or cricopharyngeal myotomy (56).

Pharyngeal Dysphagia 61

Muscular dystrophy Patients with muscular dystrophy mainly experience difficulties with the oral phase of swallowing, due to problems with mouth opening and chewing. As the disease progresses, the pharyngeal muscles become weaker, leading to residue post swallow and increased risk of choking or aspiration (59). Positional changes and modification of diet and fluids to accommodate muscle weakness helps manage dysphagic symptoms in these patients.

Myotonic dystrophy Patients with myotonic dystrophy experience a high prevalence of pharyngeal dysphagia due to impaired muscle contraction of the pharynx and poor UES function (60). Dysphagia is managed using a combination of positional and diet and fluid modification to compensate for weakened muscles.

Myasthenia gravis Myasthenia Gravis is an acquired autoimmune disorder caused by poor uptake of neuromuscular transmitter at the neuromuscular junction, resulting in muscle strength progressively declining as a movement is repeated. For example, a patient may begin chewing with normal function, but jaw strength rapidly diminishes until the patient is unable to chew. The most common pharyngeal difficulties experienced by patients with myasthenia gravis are nasal regurgitation due to poor velopharyngeal function, prolongation of laryngeal excursion and pharyngeal residue post swallow due to weakened pharyngeal and tongue muscle movements (61). While Myasthenia Gravis patients are often well managed using medications, they may experience periodic exacerbations of their disease. At this time their dysphagia may require additional support to allow patients to continue safe oral intake.

Burns

Dysphagia is a significant part of severe burn injuries and is likely to impact on poor outcomes in these patients (62). Burns may cause changes to the structural integrity of the face and oral cavity, with burn scars and contractures altering the mechanical ability to ingest oral nutrition. These injuries may increase the risk of mortality and cause dysphagia, dysphonia (voice changes) and respiratory compromise. Burns patients may also experience changes to taste sensation, either if there is damage to taste buds in the oral cavity, or zinc (responsible for mediation of taste) being metabolised differently following burn injuries. Endoscopy to visualise the oropharyngeal and laryngeal structures may provide useful information about the extent and type of trauma caused by burns injuries (62).

Managing Pharyngeal Dysphagia

Best practice in management of patients with pharyngeal dysphagia involves a multidisciplinary team. The goals of dysphagia management should be formed in consultation with the patient and carers/family and involves good communication between parties. 62 P. Claire Langdon and Kim M. Brookes

Successful dysphagia management considers the prognosis of the patient and their underlying etiology: will their dysphagia improve, will their swallowing function get worse as a progressive degenerative condition runs its course, or will the management goals be to maintain oral intake at optimum level for as long as possible? Maintaining adequate oral intake to optimise nutrition and hydration helps the person maintain their quality of life.

Maintaining Nutrition and Hydration

As previously stated, one of the main difficulties experienced by people with dysphagia is reduced ability to maintain adequate nutrition and hydration. Dysphagia is in itself, not a disease or condition, but a symptom or sign caused by an underlying etiology. For this reason, dysphagia is best managed by utilising the skills of a multidisciplinary team. The team members, and their roles are described in more detail below.

The Dysphagia Multidisciplinary Team

Gold standard management of oropharyngeal dysphagia brings together the knowledge, skills and abilities of a multidisciplinary team who view the dysphagic patient as a whole person rather than a disease or disability. Managing dysphagia well involves thorough assessment and treatment to maintain optimal nutrition, hydration and enjoyment of eating and drinking for the patient, together with respect for their autonomy and independence. Often the skill sets of several disciplines will come together and result in an innovative and comprehensive management solution that takes into account the patient‘s requirements and goals.

Medical Medical management of the dysphagic patient involves prescribing and monitoring the effectiveness of medications, monitoring nutrition and hydration through laboratory testing, ordering additional investigations – for example, chest x-rays – and referring on to specialists for additional investigations. In the hospital setting, the Consultant Physician may head up the multidisciplinary team and be responsible for the overall management of a patient‘s condition.

Medical specialties

Neurologist The neurologist has an exceptional understanding of the central and peripheral nervous system. They are often the first point of diagnosis of swallowing problems in patients with neurological disorders and work closely with the other members of the team to facilitate optimal nutrition and hydration in the patient with an underlying condition.

Pharyngeal Dysphagia 63

ENT/head and neck surgeon The Ear, Nose and Throat specialist and Head and Neck Surgeon has a body of knowledge in relation to the upper airway, larynx, laryngopharynx, oropharynx and nasopharynx. They diagnose and treat problems in these areas such as laryngeal mucosal injuries, neoplasms of the head and neck and trauma injuries.

Gastroenterologist Gastroenterologists have specialist expertise in diagnosing and managing diseases and impairments to the gastrointestinal tract. They can assess and treat gastroesophageal and laryngopharyngeal reflux, esophageal motility disorders, impairment to the functional integrity of the UES and structural changes to the patency of the esophagus.

Respiratory physician A respiratory physician specialises in conditions affecting the lungs, such as asthma, bronchitis, chronic obstructive pulmonary disease, interstitial lung disease, cystic fibrosis, lung cancer and mesothelioma. They may have interests in the areas of sleep physiology or diving medicine. Assessment of respiratory function and management of impaired function by a Respiratory Physician can have a significant impact on a dysphagic patient‘s quality of life. Normal swallowing involves a swallow apnoea, where breathing momentarily ceases during the swallow. Patients with respiratory impairment may have an impaired tolerance of swallowing apnoea, and oxygen supply in the bloodstream may be reduced as the patient struggles to coordinate the two functions. A patient who becomes short of breath while eating a meal may require supplementary oxygen when eating to maintain the oxygen saturations in their blood. A patient who quickly fatigues, may require ventilatory support. Also, numerous studies have shown an uncoupling of the normal exhalation at the end of the swallow in some patients; notably stroke, COPD and Parkinson‘s Disease patients (63-65). This impairment may predispose patients to aspiration.

Radiologist The Radiologist and Speech Pathologist work together to perform a videofluoroscopic swallow study (Modified Barium Swallow Study). The radiologist is trained to identify structural abnormalities. The speech pathologist is familiar with the functional details of oral and pharyngeal patterns during swallow and the therapeutic techniques that can be trialled to treat particular disorders (66).

Nursing Nurses have the opportunity to observe a patient over a period of time and may note signs of swallowing impairment that require further investigation. They are responsible for assisting patients with meals if they are unable to feed themselves, help position and reposition patients with difficulty maintaining an upright seated posture for meals and monitor their patients‘ oral intake. Nurses perform mouth care for unconscious or impaired patients, insert nasogastric feeding tubes and administer enteral feeds, and suction patients with tracheostomy tubes to maintain a clear airway. They can also liaise with and educate 64 P. Claire Langdon and Kim M. Brookes family members about swallowing impairments. Nurses bring their knowledge, skill, care and patience to optimise nutrition and hydration for their patients (67).

Allied health

Speech pathologist Speech Pathologists take an active role in diagnosing and treating dysphagia and in research to better understand the complex neurological phenomenon that is successful swallowing. They work with other specialists to evaluate dysphagia: Radiologists to perform videofluoroscopy/Modified Barium Swallow, ENTs to perform Fibreoptic Endoscopic Evaluation of Swallowing (FEES), Head and Neck surgeons to examine the patency of surgery for head and neck cancers, Respiratory Physicians to manage tracheostomies and other Allied Health professionals such as Dietitians in diagnosing and optimising care for patients with swallowing impairment.

Dietitian Dietitians bring their expertise in the fields of biochemistry, anatomy, physiology, food science and diet therapy together with skills in interviewing and counselling to the management of the dysphagic patient (68). They manage enteral feeding regimes, prescribe nutritional supplements, work with patients to best meet their nutritional needs while considering food preferences and dietary requirements (e.g. vegetarian, Halal) and work closely with the Speech Pathologist with patients who are transitioning from a non-oral to oral diet, or from oral feeding to enteral feeding in progressive degenerative diseases.

Occupational therapist The Occupational Therapist contributes to the dysphagia management team in helping to optimise seating and positioning for patients with motor control problems. They assess the way that patients manage eating and drinking and may provide modified eating utensils or adaptive equipment to assist patients in maintaining or regaining independence with oral intake.

Physiotherapist Physiotherapists are responsible for the provision of chest therapy for patients who are unable to clear respiratory secretions by coughing. They bring their skills and knowledge of anatomy and physiology to assist patients with movement difficulties to optimise their position for oral intake. They work with nursing and the Speech Pathologist in management of ventilator-dependent patients and patients with tracheostomy tubes in order to minimise these patients‘ risk of aspiration.

Pharmacist The Pharmacist plays an important role in managing a patient with swallowing impairment. Many medications have the side effect of xerostomia, which can lead to difficulties in the oral phase of swallowing. Some of the medications utilised in managing psychoses can have the side effect of producing tardive dyskinesia, (repetitive movements that interfere with effective swallowing). Some medications may cause an adverse reaction in Pharyngeal Dysphagia 65 patients – for example Tramadol is an effective pain medication, but may cause confusion and tremor in some patients (69). If a patient has a pharyngeal swallowing impairment, the pharmacist may be called upon to suggest alternatives to large tablets or alternative methods of administering medication: this may take the form of dermal patches, sublingual or wafer administration. Medication interactions may also lead to swallowing difficulties, particularly in elderly patients who may take multiple medications daily, and the pharmacist can advise which medications are known to have interaction effects.

Dentist The dentist plays an important role in management of oral dysphagia, as without dentition it is difficult to adequately chew and prepare a bolus. Poorly fitting dentures may also impact on eating, with stomatitis a common sequalae when ill-fitting dentures cause oral lesions. Gingivitis and periodontal disease are responsible for an increase in the bacterial load 8 in the oral cavity. While normal saliva has 10 organisms/mL, saliva from a patient with gingivitis may contain 1011 organisms/mL (70). High concentrations of bacteria aspirated into the lungs may overcome normal defences and lead to increased risk of respiratory complications (10, 71). Professional oral care has been associated with a decrease in the incidence of aspiration pneumonia in the elderly (72). The dentist also plays a role in rehabilitation of swallowing; fashioning prosthetic appliances for stroke and oral cancer patients to maximise residual function.

Instrumental Assessment of Pharyngeal Dysphagia

While the oral phase of swallowing may be visualised to a certain extent by simple observation, it is difficult to see the efficiency of the pharyngeal phase of swallowing in a patient. Laryngeal closure and airway protection, epiglottic deflection and relaxation/opening of the UES all occur ‗invisibly‘. While an experienced swallowing clinician can make educated guesses about what is occurring in the pharynx, instrumental techniques should be utilised in order to make clinical decisions about what muscle groups are impaired, whether aspiration is occurring and to ascertain and quantify the amounts of residue and aspiration that the swallow produces. The most common instrumental analyses used in assessing pharyngeal dysphagia are Videofluoroscopy/MBS, FEES and Cervical Auscultation. These procedures are discussed in more detail below.

Videofluoroscopy/Modified Barium Swallow

Videofluoroscopy is used to assess swallowing physiology as it allows visualisation and quantification of the presence and nature of oropharyngeal and cervical esophageal swallowing disorders. Videofluoroscopy maps bolus flow in relation to structural movement through the upper aerodigestive tract in real time (73). The procedure involves use of radiographic equipment and a video or digital recorder to capture the swallowing sequence. Patients are given liquids and foods mixed with a radio opaque substance (normally Barium) 66 P. Claire Langdon and Kim M. Brookes and asked to eat and drink while moving radiographic images are observed and captured. Ideally, the procedure is performed jointly by a radiologist and a speech pathologist and determines the effects of food/fluid consistency on swallowing while allowing the effectiveness of compensatory manoeuvres to be assessed (74). Videofluoroscopy is ideal to determine and quantify the presence or absence of aspiration in a patient and to visualise oral, pharyngeal and esophageal phases of the swallow. It allows the therapist to assess the effect of various compensatory moves and to measure change over time in a patient. Its limitations include that it does not provide a good view of secretion management and is a 2-dimensional representation of a 3-dimensional event. Barium is quite a dense material and impacts on taste sensation and ‗mouthfeel‘. The procedure is also not particularly representative of an actual meal: the patient is seated with equipment around them and asked to swallow to command. Effects of fatigue are difficult to capture as exposure to radiation is limited for reasons of radiation safety. Not all patients can maintain a sitting position and morbidly obese patients may not be able to be accommodated by the equipment.

Fibreoptic Endoscopic Evaluation of Swallowing (FEES)

In the past 20 years fibreoptic laryngoscopy passed transnasally has become increasingly utilised to perform objective instrumental assessment of swallowing. Studies have shown that FEES and videofluoroscopy have equivalent specificity and sensitivity in examining delayed swallow, pharyngeal residue post swallow, and penetration/aspiration of materials into the trachea (75). The procedure involves passing a flexible laryngoscope through the nostrils, over the palate and into the hypopharynx to provide a view of the larynx, pharynx and upper esophageal sphincter. Assessment of palatal function, secretion management, penetration/aspiration and post swallow residue can be made. Many signs and symptoms of dysphagia can be assessed using FEES; patients with hypernasality or nasal regurgitation, laryngeal penetration or aspiration, abnormal voice quality and vocal fold movement. FEES is excellent for quantifying amount and location of residue post swallow. Postural strategies and compensations can be trialled with the scope insitu and their effectiveness evaluated. The procedure is excellent for patients for whom radiation exposure is not suitable, for patients who cannot be moved to the radiology suite for videofluoroscopy or for patients who are morbidly obese or require special positioning, which prevents use of the equipment associated with videofluoroscopy. Contraindications for FEES include facial fractures or obstruction of the nasal passages (75). The moment of the swallow is lost with FEES, as the pharyngeal walls approximate around the scope, causing ‗whiteout‘ as the swallow occurs. This precludes observation of aspiration during the swallow and makes quantification of aspiration difficult. FEES is not a suitable procedure for patients who cannot tolerate passage of the scope, or those patients with extreme agitation or confusion. Endoscopy also provides an avenue to test laryngeal sensation: this is the Fibreoptic Endoscopic Evaluation of Swallowing with Sensory Testing (FEEST), which utilises a small puff of air delivered to the aryepiglottic folds to test the laryngeal adduction response. Poor Pharyngeal Dysphagia 67 pharyngeal squeeze and impaired sensation put patients at higher risk of aspiration or penetration compared to patients with intact sensation and movement (76).

Cervical Auscultation

Cervical auscultation is a method of listening to the sounds of swallowing using a stethoscope or microphone applied to the area of the throat immediately superior to the larynx. It is non-invasive and portable and has been described as a useful adjunct to the clinical and instrumental examination (77). It has the advantage of being easy to use and inexpensive and can be used to monitor performance throughout a meal, giving information about swallow-respiration coordination and airway protection (78). Disadvantages of cervical auscultation are that the sounds clinicians listen to have not been fully researched as to their cause and that the clinician‘s expertise and experience will impact on the sensitivity of the procedure to determine aspiration.

Rehabilitation of Pharyngeal Dysphagia

Dysphagia rehabilitation involves the skills, knowledge and abilities of a multidisciplinary team. The patient‘s nutrition and hydration must be maintained during rehabilitation: this may be achieved by oral intake alone, enteral feeding alone or by a combination of oral and enteral feeding, with gradual increase of the amount that is taken orally. In rehabilitation, instrumental evaluation of the swallow such as a videofluoroscopy or FEES is often conducted before beginning treatment. This is to help determine the underlying cause of the defective swallowing mechanism, decide what can be safely managed in terms of oral intake, and to trial different compensations to determine their effectiveness and impact on the disordered swallow. It also provides an objective baseline for treatment efficacy decisions.

Compensatory Strategies

Compensatory strategies are designed to alleviate the symptoms of dysphagia. They are often the first line of treatment because they are relatively easy and most patients can use them with minimal direction (79). They are a short-term solution that do not alter the underlying physiology of the swallowing mechanism: when they are not implemented, the dysphagic symptoms return. Compensatory strategies include: 1. Chin down – the chin is ‗tucked‘ towards the chest immediately prior to initiating the swallow. This posture narrows the distance between the tongue base and posterior pharyngeal wall, widens the valleculae and narrows the entrance to the airway. It is useful for patients with base of tongue impairment, delayed swallow initiation, oral tongue impairment or reduced airway closure (79). 68 P. Claire Langdon and Kim M. Brookes

2. Chin elevated – for patients who have difficulty in moving a bolus posteriorly, a chin elevated posture uses gravity to assist the bolus flow into the pharynx. This posture may also be useful for some patients who experience velopharyngeal insufficiency by helping to approximate the soft palate to the posterior pharyngeal wall. It should only be utilised by patients who have an intact pharyngeal swallow and good airway protection (79) due to the increased risk of the bolus entering the airway with this strategy. 3. Head turned – this compensatory posture may be useful for patients with unilateral pharyngeal or laryngeal weakness – for example, in a patient with a hemiparesis following a stroke. The head is turned towards the weaker side when swallowing. This allows the pharyngeal constrictors on the unimpaired side – the stronger side – to do the majority of the ‗work‘ in safely swallowing the bolus, directing the bolus away from the weaker or hemiparetic side. 4. Head tilted – for patients with oral weakness or insufficiency, who have an intact pharyngeal swallow, a head tilt to the stronger side allows the stronger muscles to direct the bolus. 5. Lying down (side lying) – this positioning is useful for patients who have bilateral pharyngeal damage or aspiration after the swallow due to reduced laryngeal excursion as it prevents residue in the pharynx from falling into the larynx allowing a second swallow to clear the residue into the esophagus (79). 6. Alternating liquids and solids – for the patient with reduced pharyngeal clearance and esophageal motility, alternating solids with sips of liquids can assist in ‗flushing‘ the food bolus through the esophagus to the stomach. 7. Supraglottic swallow – this compensation requires that the patient inhale, purposefully hold their breath, swallow and then exhale with increased effort post swallow. It is designed for patients who have a degree of laryngeal penetration pre-, during or after swallow. Breathing out strongly or coughing after the swallow serves to forcefully expel any material that has entered the airway. As previously discussed, the most common respiration-swallow pattern is exhalation post swallow. This pattern may be disrupted in some conditions, with inhalation post swallow observed, increasing the likelihood of material entering the respiratory tract. The supraglottic swallow imposes a conscious pattern upon the swallow, ensuring that strong exhalation drives any aspirate out of the laryngeal vestibule so that it can be safely ingested. 8. Super-supraglottic swallow – although this strategy may be confused with the supraglottic swallow, it is a little different. The patient is asked to hold their breath strongly, then to cough post swallow. The ‗strong‘ breath hold is designed to recruit the false vocal cords in the swallow attempt, adding another layer of airway protection. 9. Mendohlson manoeuvre – this involves prolonging the larynx at its highest point during a swallow – ‗catching‘ and ‗holding‘ the larynx at the apex of its trajectory. This is designed to prolong the extent and duration of UES opening (80). 10. Effortful swallow – where a patient is instructed to ―Swallow hard‖, thereby increasing the force upon the bolus to move it more effectively through the pharynx. Pharyngeal Dysphagia 69

Rehabilitation Exercises

There are several exercise programs that can help patients to improve the strength and coordination of muscles in the oropharyngeal swallow: their effectiveness generally takes from 1-6 weeks to be effective and requires pre- and post-exercise assessments (79). They are:

1. Shaker (head-lifting) exercise – involves raising the head while the subject is in a supine position (81). This exercise is designed to strengthen the suprahyoid complex of muscles (anterior belly of the digastric, mylohyoid and geniohyoid) that are responsible for laryngeal movement and UES opening when swallowing: a major component of an effective swallow. 2. Mendohlson manoeuvre – although this exercise is described in the Compensatory Strategies section, it can produce changes in the underlying physiology of the swallow. Performed as a rehabilitation exercise, the Mendohlson Manoeuvre is designed to strengthen the suprahyoid muscles involved in laryngeal excursion while also providing a passive stretch to the UES. 3. Masako manoeuvre or tongue-hold manoeuvre – increases the forward movement of the posterior pharyngeal wall at the level of the tongue base (82). This is useful when compensating for impaired base of tongue movement. 4. Effortful swallow – another exercise that can be used as a compensation strategy, but that will result in changes to swallowing physiology. The effortful swallow increases tongue base retraction and results in an increase in tongue propulsive force. It has also been shown to cause longer UES relaxation and duration of pharyngeal pressure (83) together with increased extent and duration of hyolaryngeal excursion (84). 5. Tongue strength exercises – from exercises using a biofeedback device, repetitive training that involves pressing the tongue hard against the palate has been shown to result in improvements in swallowing pressure when applied to eating and drinking. It has been noted that tongue pressure generation declines with age (85), but tongue strength can be improved with exercise (86). These exercises are designed to improve oral and pharyngeal transit times and improve swallow efficiency (79).

Surface ElectroMyoGraphy (sEMG)

Surface electromyography (sEMG) provides a record of muscle activity obtained through electrodes applied to the skin and is a non-invasive procedure that gives general information about the duration and amplitude of muscle activity associated with a functional activity such as swallowing. It gives immediate biofeedback about muscle performance to the patient and clinician to improve volitional control of a physiological process. In the case of dysphagia, patients can be taught to relax muscle tone, to contract muscles or improve coordination among different muscle groups (87). While sEMG is a useful treatment adjunct, it is not a therapy in itself; rather it provides information to the patient about their performance of rehabilitation exercises. 70 P. Claire Langdon and Kim M. Brookes

Patients who use sEMG as part of a dysphagia rehabilitation programme have electrodes applied to clean skin to capture the muscle activity of the group of muscles that their particular rehabilitation program is targeting. The feedback from the electrodes shows patients if they are increasing the strength of muscle contraction, changing the timing of the contraction, or suppressing extraneous muscle activity, such as the tremor and tongue ‗rocking‘ seen in Parkinson‘s Disease patients prior to initiation of a swallow. Surface EMG has been shown to be an efficacious adjunct to swallowing therapy, facilitating improvement in swallow physiology in a short time period, with treatment gains maintained for long periods of follow up (87).

Neuromuscular Electrical Stimulation (NMES)

The application of electrical stimulation to excite nerve or muscle is a commonly used treatment in physical therapy that has been shown to increase muscle size and improve circulation, range of motion and muscle endurance. It can only be used on muscles with the nerve still intact and facilitates muscle contraction during functional activities (88). In dysphagia rehabilitation, electrodes are applied to the bellies of affected muscles and a small current is passed through them to facilitate contraction. This, coupled with actual swallowing, is thought to result in improvements in swallow function that are greater than that which can be achieved by rehabilitation exercises alone. More than 9000 clinicians in the United States have been trained to use the technique, though it has been criticised for a lack of treatment efficacy research. In a meta-analysis of the available research, a statistically significant summary effect size in favour of NMES in rehabilitation of swallowing disorders was found (88). Recently two small randomised control trials have been published: both report NMES was superior to ‗normal‘ swallowing therapy alone in (a) stroke (89) and (b) head and neck cancer patients (90).

Surgical Management

Botulinum toxin (botox) Injection of botulinum toxin A may be considered in cases of hypertonicity of the cricopharyngeal muscle. It reportedly is a simple technique with a low complication rate (7/100) having an onset around day 7 and an offset of at least 4 months. It may be preferable over surgical myotomy because of the low risk, low cost and effectiveness of the procedure (91). The effect of botulinum toxin is temporary, and the procedure will need to be repeated to maintain improvements. It is possible that Botox is useful to determine whether the cause of a patient‘s dysphagia is due to cricopharyngeal hypertonicity: if the swallowing impairment is alleviated by Botox, then a myotomy may be efficacious as a more permanent solution. It is essential that the injection is performed with accuracy and at the lowest effective dose, as the toxin may spread to adjacent tissues which can cause voice and airway problems (34).

Pharyngeal Dysphagia 71

Cricopharyngeal myotomy This procedure involves cutting the cricopharyngeus muscle using either an endoscopic or external approach and, permanently opening the upper esophageal sphincter (34). Although there is little agreement in the literature regarding the indications for cricopharyngeal myotomy (56) it is reported that patients with Zenker‘s diverticulum and oculopharyngeal dystrophy have a good response, though patients with reflux should have this controlled prior to myotomy being undertaken (92). It is recommended for hypertonicity of the cricopharyngeus muscle as determined by esophageal manometry. Possible complications of the procedure include haemorrhage, haematoma, damage to the recurrent laryngeal nerve, infection and development of a pharyngocutaneous fistula (34).

Repair of Zenker’s diverticulum This may be achieved via open surgery or endoscopically, but carries a risk of complications. A study into the outcomes in patients with surgical repair of Zenker‘s found 7/13 had postoperative pharyngeal dysfunction and 3/11 patients who underwent radiological evaluation of their repair were shown to have leaks. Of patients who had endoscopic stapling repair of their Zenker‘s 1/3 were found to have pharyngeal dysfunction following the intervention (93).

Surgical reduction of osteophytes In patients with severe dysphagia from osteophytes, surgical osteophytectomy is an effective option (47).

Teflon injection into impaired vocal fold This technique is used in patients whose laryngeal adduction for airway protection has not improved spontaneously or cannot be increased via therapy (66). While spontaneous recovery of swallowing is possible for patients with impaired vocal fold movement, this is usually achieved by the unimpaired cord moving past the midline to approximate closure. This generally occurs in the first few months post insult. If spontaneous recovery has not occurred by 6 months post the initial insult, patients may be considered for Teflon injections to improve functional capacity. Teflon is injected into the vocal fold to ‗bulk‘ it out so that the distance that the unimpaired fold has to adduct is decreased.

Conclusion/Summary

While there are many causes of pharyngeal dysphagia, it is an exciting time to be working in the area of its diagnosis, management and remediation. New instrumental techniques such as functional magnetic resonance imaging (fMRI), positron emission technology (PET) scans and transcranial magnetic stimulation (TMS) are allowing greater visualisation of the neural networks that are involved in normal swallowing function. Better understanding of the underlying neural substrates allows greater insight into the mechanisms involved in normal deglutition and are important in understanding how best to rehabilitate dysphagia. A generation ago, swallowing dysfunction was managed by either prescribing modified diet and fluids or bypassing the swallowing system using enteral feeding. The goal 72 P. Claire Langdon and Kim M. Brookes of management was seen as prevention of aspiration at all costs. More recent studies and greater understanding of the sequence of events that lead to development of respiratory infections have allowed introduction of such protocols as Free Water, where patients who have demonstrated aspiration are allowed to consume water as an alternative to thickened liquids. Better understanding of neurological plasticity allows swallowing clinicians to work with a damaged system using the principles of physical therapy to improve functional outcomes.

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[68] Curran, JE. Nutritional considerations. In: M. E. Groher, editor. Dysphagia: Diagnosis and management. Boston: Butterworth-Heinemann; 1992. [69] Kaye, K. Trouble with tramadol. 2004 [updated 2004; cited 2009 March 19]; Available from: http://www.australianprescriber.com/magazine/27/2/26/7/. [70] Mojon, P. Oral health and respiratory infection. J Can Dent Assoc., 2002 Jun, 68(6), 340-5. [71] Marik, PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med., 2001 Mar 1, 344(9), 665-71. [72] Adachi, M; Ishihara, K; Abe, S; Okuda, K; Ishikawa, T. Effect of professional oral health care on the elderly living in nursing homes. Oral Surg Oral Med Oral Pathol Oral Radiol Endod., 2002 Aug, 94(2), 191-5. [73] Martin-Harris, B; Jones, B. The videofluorographic swallowing study. Phys Med Rehabil Clin N Am., 2008 Nov, 19(4), 769-85, viii. [74] Palmer, JB; Drennan, JC; Baba, M. Evaluation and treatment of swallowing impairments. Am Fam Physician., 2000 Apr 15, 61(8), 2453-62. [75] Leder, SB; Murray, JT. Fiberoptic endoscopic evaluation of swallowing. Phys Med Rehabil Clin N Am., 2008 Nov, 19(4), 787-801, viii-ix. [76] Aviv, JE; Spitzer, J; Cohen, M; Ma, G; Belafsky, P; Close, LG. Laryngeal adductor reflex and pharyngeal squeeze as predictors of laryngeal penetration and aspiration. Laryngoscope, 2002 Feb, 112(2), 338-41. [77] Borr, C; Hielscher-Fastabend, M; Lucking, A. Reliability and validity of cervical auscultation. Dysphagia, 2007 Jul, 22(3), 225-34. [78] Cichero, J; Murdoch, B (Ed.). Dysphagia: theory, foundation and practice. Chichester: John Wiley and Sons; 2006. [79] Logemann, JA. Treatment of oral and pharyngeal dysphagia. Phys Med Rehabil Clin N Am., 2008 Nov, 19(4), 803-16, ix. [80] Kahrilas, PJ; Logemann, JA; Krugler, C; Flanagan, E. Volitional augmentation of upper esophageal sphincter opening during swallowing. Am J Physiol., 1991 Mar, 260 (3 Pt 1), G450-6. [81] Shaker, R; Kern, M; Bardan, E; Taylor, A; Stewart, ET; Hoffmann, RG; et al. Augmentation of deglutitive upper esophageal sphincter opening in the elderly by exercise. Am J Physiol., 1997 Jun, 272(6 Pt 1), G1518-22. [82] Fujui, M; Logemann, J. Effect of the tongue hold maneuver on posterior phayrngeal wall movement during deglutition. American Journal of Speech-Language Pathology, 1996, 5(1), 23-30. [83] Hiss, SG; Huckabee, ML. Timing of pharyngeal and upper esophageal sphincter pressures as a function of normal and effortful swallowing in young healthy adults. Dysphagia, 2005, Spring, 20(2), 149-56. [84] Hind, JA; Nicosia, MA; Roecker, EB; Carnes, ML; Robbins, J. Comparison of effortful and noneffortful swallows in healthy middle-aged and older adults. Arch Phys Med Rehabil., 2001 Dec, 82(12), 1661-5. [85] Robbins, J; Levine, R; Wood, J; Roecker, EB; Luschei, E. Age effects on lingual pressure generation as a risk factor for dysphagia. J Gerontol A Biol Sci Med Sci., 1995 Sep, 50(5), M257-62. Pharyngeal Dysphagia 77

[86] Robbins, J; Kays, SA; Gangnon, RE; Hind, JA; Hewitt, AL; Gentry, LR; et al. The effects of lingual exercise in stroke patients with dysphagia. Arch Phys Med Rehabil., 2007 Feb, 88(2), 150-8. [87] Crary, MA; Groher, ME. Basic concepts of surface electromyographic biofeedback in the treatment of dysphagia: A tutorial. American Journal of Speech-Language Pathology, 2000, 9, 116-25. [88] Carnaby-Mann, GD; Crary, MA. Examining the evidence on neuromuscular electrical stimulation for swallowing: a meta-analysis. Arch Otolaryngol Head Neck Surg., 2007 Jun, 133(6), 564-71. [89] Permsirivanich, W; Tipchatyotin, S; Wongchai, M; Leelamanit, V; Setthawatcharawanich, S; Sathirapanya, P; et al. Comparing the effects of rehabilitation swallowing therapy vs. neuromuscular electrical stimulation therapy among stroke patients with persistent pharyngeal dysphagia: a randomized controlled study. J Med Assoc Thai., 2009 Feb, 92(2), 259-65. [90] Ryu, JS; Kang, JY; Park, JY; Nam, SY; Choi, SH; Roh, JL; et al. The effect of electrical stimulation therapy on dysphagia following treatment for head and neck cancer. Oral Oncol., 2008 Dec 16. [91] Moerman, MB. Cricopharyngeal Botox injections: Indications and technique. Curr Opin Otolaryngol Head Neck Surg., 2006, 14(6), 431-6. [92] Sivarao, DV; Goyal, RK. Functional anatomy and physiology of the upper esophageal sphincter. Am J Medicine., 2000, 108(4A), 27S-37S. [93] Sydow, BD; Levine, MS; Rubesin, SE; Laufer, I. Radiographic findings and complications after surgical or endoscopic repair of Zenker's diverticulum in 16 patients. AJR Am J Roentgenol., 2001 Nov, 177(5), 1067-71.

Chapter III

Effects of Maxillofacial Disorders on Pharyngeal Structures and Orthodontic Treatment Modalities

1Nihat KILIÇ* and 2Husamettin OKTAY 1, 2Department of Orthodontics, Faculty of Dentistry, Atatürk University, Erzurum, Turkey.

Summary

The human body constitutes a functional entity, no part of which can be varied without entailing some changes in other parts. Similarly, the facial skeleton and the dentition are functional parts of the skull as a whole. The stomatognathic system consists of mouth, upper and lower jaws, teeth, upper respiratory tract, pharynx, and the other structures related with mastication, deglutition, respiration, speech, and the functions in a functional entity according to functional matrix theory. Developmental disorders in any organ of this system and/or functional aberrations will also affect the other components. The relationships between respiratory disturbances and maxillofacial growth and development have been the center of interest among orthodontists for years. Animal and human studies have demonstrated that a close relationship exist between nasal respiration and dentofacial form and development. Mouth-breathing causes serious negative effects on the normal development of nasomaxillary and craniofacial structures. Maxillofacial abnormalities are related with the nasal and pharyngeal problems including impaired nasal respiration, mouth breathing, pharyngeal infections, breathing disturbances and even conductive hearing loss. This chapter aimed to evaluate the effects of the developmental disturbances in maxillofacial region on the pharyngeal and neighboring structures. The present paper will also assess the effects of orthodontic and/or orthopedic approaches such as maxillary protraction, rapid maxillary expansion, activator, headgear, and etc.

* Corresponding author: Atatürk Üniversitesi Diş Hekimliği Fakültesi Ortodonti Anabilim Dalı, 25240 Erzurum, TURKEY, E-mail: [email protected], Phone Numbers:, Business: +90.442.2311810, Business fax: +90.442. 2312270 - 2360945 80 Nihat KILIÇ and Husamettin OKTAY

Introduction

Orthodontics is a special branch of dentistry concerning with teeth irregularities, malocclusions, and facial deformities. Orthodontics also includes dentofacial orthopedics, which is used to correct the problems involving the growth of jaws. Orthodontics is formally defined by the American Association of Orthodontics as ―Orthodontics is the area of dentistry concerned with the supervision, guidance and correction of the growing or mature dentofacial structures, including those conditions that require movement of teeth or correction of malrelationships and malformations of their related structures and the adjustment of relationships between and among teeth and facial bones by the application of forces and/or the stimulation and redirection of functional forces within the craniofacial complex‖. According to this definition, orthodontists are qualified dentists who can diagnose, prevent and treat dental, jaw and facial irregularities. The form and function of pharynx and treatment approaches of malformed and malfunctioned pharyngeal structures have been main concern of orthodontists for many years. This issue concerns not only orthodontists, but also medical practitioners, especially otolaryngologists. For example, naso-respiratory function and its relation to craniofacial growth are of great interest today, not only as an example of basic biological relationship of form and function but also because of great practical concern to pediatricians, otorhinolaryngologists, allergists, speech therapists, orthodontists, and other members of health-care community as well (1). Weider (2), an otorhinolaryngologist, stated in the beginning of an article that ―When I (D. J. W) began to practice otolaryngology at the Dartmouth Hitchcock Medical Center in April of 1974, I began receiving referrals from orthodontic colleagues in the local area. These referrals were to see if I could ascertain what might be the cause of their obligate mouth breathing. They also wanted me to perform surgery to correct the problem if possible. It was their feeling that upper airway obstruction lead to, or at-least contributed to, dental malocclusion of various types.‖ Facial skeleton and the dentition are functional parts of the skull as a whole. The stomatognathic system consists of mouth, upper and lower jaws, teeth, upper respiratory tract, pharynx, and the other structures related with mastication, deglutition, respiration and speech. Developmental disorders in any organ of this system and/or functional aberrations will also affect the other components, since human body constitutes a functional entity and no part of which can be varied without entailing some changes in other parts. The relationships between naso-respiratory disturbances and maxillofacial growth and development have been the center of interest among orthodontists for years. Animal and human studies have demonstrated that a close relationship exists between nasal respiration and dentofacial form and development (1,3-7). Mouth-breathing causes serious negative effects on the normal development of nasomaxillary and craniofacial structures. Maxillofacial abnormalities are related with nasal and pharyngeal problems including impaired nasal respiration, mouth breathing, pharyngeal infections, breathing disturbances and even conductive hearing loss. This chapter aimed to evaluate main maxillofacial developmental disturbances related with pharyngeal and neighboring structures and their effects on stomatognathic system. The present paper will also assess the effects of Effects of Maxillofacial Disorders on Pharyngeal Structures... 81 orthodontic and/or orthopedic approaches such as maxillary protraction, rapid maxillary expansion, activator, headgear, etc. on these structures. The subject headings are as follows:

1. Effects of mouth breathing on maxillofacial structures 2. Skeletal and dental abnormalities and treatment options related with maxilla: 2.1. Effects of maxillary retrusion on pharyngeal structures 2.2. Effects of maxillary protraction treatment on pharyngeal structures 2.3. Effects of maxillary constriction on naso-pharynx and hearing 2.4. Effects of RME on nasal airflow and breathing 2.5. Effects of RME on nasopharyngeal or respiratory diseases 3. Skeletal and dental abnormalities and treatment options related with mandible: 3.1. Effects of mandibular retrusion and/or deficiency on pharyngeal structures 3.2. Effects of functional appliances on pharyngeal structures 4. Effects of maxillomandibular abnormalities on sleep-disordered breathing and treatment options: 4.1. Effects of Mandibular anterior repositioning devices on OSA 4.2. Effects of Rapid maxillary expansion (RME) appliances on OSA

1. Effects of Mouth Breathing on Maxillofacial Structures

The final morphology of maxillofacial skeleton and dentition depends on the effectiveness of hereditary and environmental factors. The source of growth potential is genetic. Heredity controls both the end result and rate of progress toward the end result. Genetic factors most likely play a leading role in the final morphology of maxillofacial skeleton and dentition. However, the actual outcome of growth and development depends on the interaction between the genetic potential and environmental influences. Environmental factors may modify genetically determined growth pattern. According to the functional matrix theory, there is an absolute influence of functional spaces on craniofacial growth. This theory stressed that craniofacial growth is the result of both changes in the "capsular matrices", causing spatial changes in the position of bones (translation), and in the "periosteal matrices", causing more local changes in the size and shape of skeleton (remodeling). Naso- and oro-pharyngeal cavities play a morphogenetic role in the growth of maxillo-facial skeleton. As the volume of these functioning spaces increases, the surrounding capsule expands and the embedded macro-skeletal units are passively translated in space. Nose breathing is the natural way of normal breathing in humans. Mode of breathing has been subjected to tremendous researches. According to our knowledge, the pioneer clinician dealt with the association between mouth breathing and jaw deformities is an orthodontist, Dr. Norman W. Kingsley (8). The space of pharynx and nasal airway is dependent on the skeletal dimensions and morphology of naso-maxillary complex, naso-pharynx, and oro-pharynx. Unfavorable morphological and/or functional factors may result in increased airway resistance, thus a 82 Nihat KILIÇ and Husamettin OKTAY change from nose to mouth breathing may occur. The functional oropharyngeal airway is the critical factor for the development of resistance to airflow (9). Furthermore, the soft tissue thickness of these areas is also important for the development of resistance to airflow. Naso- pharyngeal airway size can be defined as the shortest distance from the most anterior aspect of the adenoids to the most posterior aspect of the soft palate in a relaxed position (10). Waldeyer‘s lymphatic ring constructed by two kinds of tissues (tonsils and adenoids) is of particular significance for switching from nose to mouth breathing due to changes in resistance to air flow. Size of nasal airway is another important factor on nasal airflow. Warren et al. (11) assessed the relationship between nasal airway patency and nasal airflow rate, using the pressure-flow technique to estimate nasal cross-sectional size and nasal airflow rate in 30 normal and 82 nasally impaired adults. These authors clearly demonstrated that size of airway influences airflow rate when the smallest nasal cross-sectional area is under 0.4 cm2. The data suggest that the nose becomes flow-limiting when it is less than 0.18 cm2. Depending on the cause of obstruction, mouth breathing condition can last for a short period of time or be virtually permanent. Habitual mouth breathing, which is not related with upper airway obstruction, may develop in combination with incompetent lip closure, increased overjet, or open-bite. Airway obstruction, coupled with loss of lingual and palatal pressure of the tongue, produces alterations in the mouth architecture. In the mouth breathing individuals, open mouth posture allows an oral airway to be maintained, which results in the tongue being lower in the intermaxillary space and simultaneously increasing the relative influence of the buccal musculature on the unsupported maxillary posterior teeth. The positioning of tongue also plays an important role in mandibular development. (12-14) Although there is a huge block of clinical and experimental studies, effects of mouth breathing on maxillofacial structures has been debated. Airway obstruction due to blockage of nasal and/or pharyngeal cavities leads to mouth breathing, which in turn causes postural alterations of tongue, lower jaw, and head and abnormal growth of maxillo-facial skeleton. Clinical studies have demonstrated that children with obstructed airway exhibit a dentofacial morphology which differs from that of non-obstructed controls (15-16). Linder-Aronson (16) evaluated the facial and dental morphology of the children with obstructed upper airway, mouth breathing and enlarged adenoids, and showed that the children with large adenoids have an increased anterior facial height, a large angle between the upper and lower jaws, a narrower upper dental arch, a tendency for crossbite, and retroclined upper and lower incisors. One year after the adenoidectomy operation of these children, a tendency toward ‗normalization‘ of their dentofacial measurements was observed. According to Bresolin et al. (17), the mouth breathers‘ maxillas and mandibles were more retrognathic. Palatal height was higher, and overjet was greater in mouth breathers. Overall, mouth breathers had longer faces with narrower maxillae and retrognathic jaws. According to Graber (18) and Harvold et al. (7), constricted upper dental arch may result from abnormal functions such as abnormal breathing pattern. Behlfelt et al. (5,19) found that the patients with enlarged tonsils had narrower upper dental arch and more posterior crossbite than normal children. Löfstrand-Tideström et al. (20) reported that patients having nasal obstruction and oral breathing had narrower upper dental arch and more posterior crossbite Effects of Maxillofacial Disorders on Pharyngeal Structures... 83 than normal children. Oulis et al. (21) stated that 47% of the cases with nasal obstruction had maxillary constriction and posterior crossbite. Corruccini et al. (22) showed a correlation between posterior crossbite and mouth-breathing. On the other hand, nasal obstruction leading to mouth breathing results in not only the changes in tongue and lip positions but also open mouth posture, downward and backward rotation of mandible, long-face, constricted and V-shaped maxillary dental arch, and an increased frequency of posterior crossbite (1,3-7,19) (Figure 1). Experimental animal studies (3,7,23) indicated that altered breathing pattern actually cause a change in dentofacial morphology. Harvold et al. (23) blocked nasal valves of Macaca mulattas with silicon plugs to develop mouth breathing. The animals generally adapted their new breathing mode by maintaining of open mouth. Although the authors stressed that the response to mouth breathing was not uniform among animals, a narrow mandibular dental arch, a decreased maxillary dental arch length, a tendency to develop a notch in the upper lip, increased face height, steeper mandibular plan angle, and larger gonial angle were generally observed findings in mouth breathing animals. Accordingly, the morphological changes in the orofacial region, facial skeleton and dental occlusion did vary from one animal to another. According to Timms (24), mouth breathing has several negative effects on human body. This author claimed that long-lasting mouth breathing may cause increased caries and periodontal disease, reduced nasal functions, increased naso-pharyngeal infections, disturbances in the rhythm between inspiration and expiration with imbalances of diaphragmatic and thoracic respiration, skeletal developmental disturbances including pigeon chest, kyphosis, and scoliosis, detrimental effects on the lungs such as emphysema, bronchiectasies, chronic bronchitis and asthma, and several adverse systemic effects on the nervous system, blood circulation system and heart, respiratory system, and gastric system.

Figure 1. Profile view of a subject having mouth-breathing. 84 Nihat KILIÇ and Husamettin OKTAY

In contrast with the studies mentioned above, some researchers including Tulley (25), Shanker et al. (26), Kluemper et al. (27), Vig et al. (12), O'Ryan et al. (28), failed to show the effect of mouth breathing on dentofacial morphology. In summary, mouth breathing subjects may have the following two-dimensional maxillofacial problems as compared with the normal breathing subjects:

1. Retrognathic maxilla and mandible (17,29) 2. Increased total facial height (16,17,30,31 ) 3. Increased lower anterior facial height (30-33) 4. Increased mandibular plane angle (16,17,29,30,33,34) 5. Decreased facial prognathism (16,17,35) 6. Increased gonial angle (17) 7. Class II malocclusion tendency (36,37) 8. Increased ANB angle (38). 9. Tipping of the palate (16,17,30,39) 10. Anterior open-bite tendency (40,41) 11. Reduced transverse dimensions with or without crossbite (5,17,19,20,42,43) 12. Narrowed face (7,23) 13. Postural alterations such as open lips (41), more inferior and anterior tongue (16), and posterior rotation of mandible (16,31,33,44). 14. Retroclination of upper and lower incisors. (16) 15. Greater extension of the head related to the cervical spine, reduced cervical lordosis (38).

2. Skeletal and Dental Abnormalities and Treatment Options Related with Maxilla

In this heading, the effects of sagittal and transversal anomalies on pharyngeal structures will be hold. In sagittal direction, effects of maxillary retrusion and maxillary protraction treatment will be reviewed. In transversal direction, the effects of maxillary constriction on naso-pharyngeal structures, nasopharyngeal and hearing problems, and the effect of the unique treatment, RME, on naso-pharyngeal structures will be evaluated.

2.1. Effects of Maxillary Retrusion on Pharyngeal Structures

Maxillary retrusion is characterized by underdeveloped maxilla in sagittal direction. In the subjects with maxillary retrusion, SNA angle (relating maxilla with anterior cranial base) is decreased. Class III patients often show an anterior crossbite with a concave soft-tissue profile, and can exhibit a variety of skeletal and dental components. Skeletal manifestations of the malocclusion include: a normally positioned maxilla and prognathic mandible, retrusive maxilla and normal positioned mandible, and retrusive maxilla and prognathic mandible (45). The appearance of a negative horizontal overlap of the incisors often Effects of Maxillofacial Disorders on Pharyngeal Structures... 85 stimulates the parents for orthodontic treatment. Clinically, these patients have a retrusive upper face and a protrusive lower face, causing a concave facial profile. During the growth of nasomaxillary complex, forward movement of maxilla allows the enlargement of naso-pharynx and oro-pharynx to accommodate the increased respiratory functional demands of growing children. One can speculated that maxillary retrusion results in narrowed pharyngeal dimensions, especially nasopharyngeal dimensions, since a close relationship exists between maxilla and nasopharyngeal structures. Interestingly, effects of maxillary retrusion on pharyngeal structures have been subjected only in limited studies (15,46,47). Actually, there is no well-designed study which primarily aimed to investigate structural changes in nasopharyngeal airway dimension in cases with maxillary retrusion. Two-dimensional (15,47) or three-dimensional (46) cephalometric images have been used for evaluation of pharyngeal and dentofacial structures of the cases with maxillary retrusion. Ceylan and Oktay (15) investigated the pharyngeal size on lateral cephalometric head films of 90 subjects having different anteroposterior jaw relationship, namely 30 subjects with normal jaw relationships, 30 with Class II relationship due to maxillary protrusion, mandibular retrusion, or combination of both, 30 with Class III relationship due to maxillary retrusion, mandibular protrusion, or combination of both. They found that nasopharyngeal area was not affected by the changes in anteroposterior jaw relationship. Oropharyngeal area, however, became smaller in subjects having Class II jaw relationship, but this area did not show any significant change in Class III subjects. Arslan et al. (47) evaluated craniofacial and nasopharyngeal airway morphology of 10 cases with hypohidrotic ectodermal dysplasia and maxillary retrusion. These authors concluded that the subjects with hypohidrotic ectodermal dysplasia have smaller pharyngeal and upper airway dimensions because of the posteriorly positioned hyoid bone. Alves et al. (46) used three-dimensional computed tomography and compared the upper airway spaces of Class III subjects with those of Class II. They observed no significant difference in the linear and angular measurements of both groups. In Apert's syndrome and Crouzon's disease, which are characterized by severe maxillary hypoplasia, constriction of upper airway including the nasal cavity and velopharynx may be the source of upper-airway obstruction observed in these patients (48,49) Several predisposing factors have been suggested for the obstruction of naso-pharyngeal airways. Hypertrophied adenoids and tonsils, chronic and allergic rhinitis, environmental irritants, congenital nasal deformities, nasal traumas, polyps, and tumors are considered as main predisposing factors for the development of obstruction of airways (50). Because the dentofacial and pharyngeal structures have a close relationship, a mutual interaction can be expected to occur between them (51,52). The literature presents the skeletal malocclusions as an etiology for airway morphology changes and/or vice versa. As a conclusion, it is impossible to make a precise decision that pharyngeal structures were affected by the maxillary retrusion, since there are limited numbers of studies on this subject and their sample sizes are small.

86 Nihat KILIÇ and Husamettin OKTAY

2.2. Effects of Maxillary Protraction Treatment on Pharyngeal Structures

The objective of early Class III treatment is to create an environment in which a more favorable dentofacial growth and development can occur. Primary clinical objectives of early Class III treatment are correction of anterior crossbite, obtaining normal over-jet, correction of concave skeletal and soft tissue profile, and obtaining well-balanced dento-skeletal relationships. Main goals of the early Class III treatment can be summarized as follows: (I) preventing progressive, irreversible soft tissue or bony changes; (II) improving skeletal discrepancies and providing a more favorable environment for future growth; (III) improving occlusal function; (IV) simplifying phase II comprehensive treatment and minimizing the need for orthognathic surgery; and (V) providing more pleasing facial esthetics, thus improving the psychosocial development of a child (45). Maxillary protraction appliances (MPA) have been commonly used for the treatment of skeletal Class III malocclusions with maxillary hypoplasia (retrusion) since 1960 (53). Protraction of maxilla with a facemask is a common treatment procedure for this skeletal problem (Figure 2). The primary aim of this procedure is to obtain well balanced faces by enhancing growth of the midfacial structures (54). Maxillary protraction generally requires 300-600 g force per side which produced by pulling force of elastics. Patients wear the appliance at least 12 hours a day. The effects of treatment with such orthopedic appliances have been extensively investigated and reported to be as follows: acceleration of forward growth of the maxilla with a counterclockwise rotation, forward movement of the maxillary dentition, retardation of mandibular growth and backward movement of the mandible with a clockwise rotation (56,57).

Figure 2. A conventional maxillary protraction appliance (Facemask appliance). Effects of Maxillofacial Disorders on Pharyngeal Structures... 87

Some authors (57-60) used the maxillary protraction appliances in conjunction with rapid maxillary expansion (RME), and the others (55,61,62) treated their patients by maxillary protraction only. Although it is impossible to make a precise decision that pharyngeal structures were affected by the maxillary retrusion as stated above, effects of maxillary protraction appliance with and without RME therapy on nasopharyngeal structures have been evaluated in some studies. The relevant literature consisted of short-term (63-66) and long- term studies (67). In a short-term study of Hiyama et al. (63), twenty five children (mean age: 9.8 years) with Class III malocclusion were undergone maxillary protraction therapy, and their superior upper-airway dimensions were increased by forward maxillary growth. They suggested that enhanced maxillary growth in growing patients with protraction treatment could contribute to an increase in upper-airway dimensions and improve the respiratory function of patients with maxillary hypoplasia. Sayinsu et al. (64) demonstrated that limited maxillary widening together with protraction of the maxilla in 19 children with maxillary retrusion increased nasopharyngeal dimensions, but not oropharyngeal airway dimensions. These results demonstrated that maxillary expansion together with protraction of the maxilla improved naso- and oropharyngeal airway dimensions in the short term. Kilinc et al. (65) found that maxillary expansion together with protraction of the maxilla improved naso- oropharyngeal airway dimensions. In a recent paper, Oktay and Ulukaya (66) evaluated the effects of face mask treatment on the size of upper airway passage in children with maxillary retrusion, and found that maxillary protraction caused the upper-airway dimensions to increase. According to our knowledge, long-term nasopharyngeal effects of maxillary protraction subjected only in one study (67). This long-term evaluation revealed that maxillary protraction therapy improved nasopharyngeal airway dimensions, and favorable effects of the treatment remained over the post-treatment period of 4 years.

2.3. Effects of Maxillary Constriction on Naso-Pharynx and Hearing

Transverse maxillary constriction and accompanying posterior crossbite is a common malocclusion encountered clinically (Figure 3). The prevalence of this problem ranges from 2.7% to 23.3% (34,44,68,69). In most cases, insufficient maxillary arch width accounts for the transverse discrepancy (70-72). The transverse dimension of the maxilla is defined by the maxillary skeletal base and the inclination of the buccal segment surrounded by alveolar bone (73). Generally, three associations have been suggested between maxillary constriction and the problems in nose, pharynx, and ear. The first association has been made between maxillary constriction and pharyngeal problems. This association was generally based on the obstruction of normal breathing and presence of abnormal breathing pattern, namely mouth breathing which commonly seen in cases with maxillary constriction (74). Naso-respiratory function and its relation to craniofacial growth are of great interest of the practitioners since this relationship is practically concerned with to medical doctors, orthodontists, and other members of health-care community as well (1). 88 Nihat KILIÇ and Husamettin OKTAY

Figure 3. Transverse maxillary constriction and accompanying posterior crossbite.

Enlarged tonsils and adenoids are one of the main predisposing factors for the development of posterior crossbite and narrowness of upper dental arch (5,19). An association between mouth breathing and maxillary constriction-posterior crossbite tendency has been reported by many authors (7,18,20,22). Nasal obstruction may result in maxillary constriction and posterior crossbite up to 47 % of the cases (21). The subjects with maxillary constriction have significantly higher nasal airway resistance than those with normal occlusion (75). Nose provides proper humidification, filtration and warming of inspired air. Untreated air inspiration in patients having mouth-breathing and maxillary constriction can contain risky particles and pollutants, and may be detrimental on oropharyngeal soft tissues. For this reason, naso-respiratory tissues of these children are more susceptible to infections or other complications of naso-respiratory diseases (76,77). A few isolated epidemiologic studies were encountered in the literature, which investigated possible prevalence of respiratory diseases in growing children with maxillary constriction and impaired nasal respiration (24,76-80). Respiratory infections, cold, sore throat, and allergic rhinitis may develop in most of the children with maxillary constriction and/or poor nasal breathing (76,77). Timms (78,79) reported that the children with maxillary constriction and posterior crossbite had three times more diseases such as upper respiratory tract infection, allergic rhinitis, and asthma than the patients had normal maxillary development. Allergic rhinitis and asthma were associated with divergent facial growth pattern and posterior crossbite (17,81,82). The second association has been made between maxillary constriction and ear problems such as middle ear effusion, otitis media and conductive hearing loss. This relationship based on three factors including increased pharyngeal infections due to abnormal breathing pattern, Eustachian tube dysfunctions due to improper functions of tensor veli palatini and levator veli palatini muscles, and close anatomical and functional relationships among palate, mouth, pharynx, tongue, nose and ear (74). It has been postulated that the close relationships among palate, mouth, nose, pharynx, Eustachian tube, and ears may be a causative factor on conductive hearing loss. Kim et al. Effects of Maxillofacial Disorders on Pharyngeal Structures... 89

(83) found a close relationship between the presence of high palatal vault and early recurrent acute otitis media in young children. According to Kemaloglu et al. (84), development of Eustachian tube is associated with the development of cranial base and nasomaxillary complex, and maxillary depth has determinative effects on the length of this tube. These authors hypothesized that any cessation or aberration in these parts of the craniofacial skeleton cause corresponding imbalances in the Eustachian tube, which may predispose to otitis media. Abnormal or impaired Eustachian tube functions (i.e., impaired opening or closing, defective mucociliary clearance) may cause pathological changes in middle ear that in turn can lead to hearing loss and/or other complications of the otitis media (85,86). These pathological changes include recurrent acute otitis media and otitis media with effusion. If the tube is blocked, air in middle ear is absorbed into the mucosal cells with loss of pressure, increasing concavity of tympanic membrane and progressive deafness (87). Braun (88) stated that maxillary constriction could affect Eustachian tube and middle ear, and thus may cause conductive hearing loss. Rudolph (87) speculated that abnormal or impaired Eustachian tube functions seen more frequently in children having high palatal arches (constricted maxillary arches) as well as malformations of the palate and nasopharynx that might predispose to otitis media. A recent study carried out by Chiary et al. (89) revealed that the patients with maxillary constriction had the largest adenoids and negative pressure in the middle ear. Laptook (90) reported that there was a severe hearing loss (up to 50 decibel) in a child with constricted maxillary arches and mouth breathing. Villano et al. (91) showed that conductive hearing loss occurred in the children with palatal constriction. These authors demonstrated by video-otoscopy the presence of a thick mucous exudate in variable quantities at the pharyngeal entrance of the tube in all cases. Kilic et al. (92,93) and Ceylan et al. (94) revealed that the children with maxillary constriction and deep palatal vault had a degree of conductive hearing loss varied from minimal to severe. Kilic et al. (92,93), Ceylan et al. (94), Taşpinar et al. (95), and Cozza et al. (96) explained existence of conductive hearing loss in children who had narrowed maxillary arches with abnormal or decreased functions of Eustachian tube. The third association has been suggested between maxillary constriction and breathing problems such as obstructive sleep apnea (97,98). This association will be explained in the following papers of this chapter.

2.4. Effects of RME on Nasal Airflow and Breathing

RME has been used as a routine clinical procedure in orthodontics, with its main purpose to expand the maxilla in young patients who had transversal maxillary constriction and deep palatal vault and accompanying cross-bite and crowding. This treatment procedure is carried out with an appliance having an expansion screw welded to the bands on the first premolars and first molars (Figure 4). The expansion screw was periodically activated per day, and the resulting force (0.9–4.5 kg) causes midpalatal suture to open and the maxillary bones to diverge from each other (Figure 5). 90 Nihat KILIÇ and Husamettin OKTAY

Figure 4. Rapid maxillary expansion (RME) appliance.

Figure 5. Occlusal film showing midpalatal suture opening after RME therapy.

Effects of RME on nasal airflow and breathing have been subjected in several studies. RME separates maxillary halves, moves the outer walls of nasal cavity laterally, and these changes produce an increase in intranasal capacity. The studies demonstrated that the increase in transversal nasal dimensions after RME ranged from 2 to 4 mm (99,100). Babacan et al. (101), Doruk et al. (102) and Palaisa et al. (103) evaluated the effects of RME on nasal volume, and found significant increases. There is a general consensus among the orthodontists that transversal skeletal maxillary width and concomitantly nasal width significantly increases after RME (100,104-110). The increase in nasal cavity width occurs particularly at the nasal floor adjacent to mid-palatal suture (99,111). It has been well documented in clinical studies (75,112,113) that the increase in nasal cavity width and the Effects of Maxillofacial Disorders on Pharyngeal Structures... 91 decrease at nasal airway resistance improves nasal breathing after RME. The decrease at nasal airway resistance due to maxillary expansion may reach up to 45 percent (75,109,114,115). Buccheri et al. (116) investigated pharyngeal airway changes after RME, and found that RME caused an increase in pharyngeal lumen and an improvement in nasal breathing. Although RME increases both nasal and pharyngeal airway dimensions and facilitates normal breathing, the role of this procedure on breathing mode is still remains debatable (117). Some clinicians (76,77,117) observed that RME caused breathing mode changes in the most of mouth-breathing children. Compadretti et al. (117) stated that ‗‗… Nasal dimensions influence the ability to breathe through the nose. However, the evidence that a percentage of children with adequate nasal airways are predominantly oral breathers also indicates that learning influences mode of respiration.‘‘ Some authors reported contrary findings related with cross-sectional area of nasal cavity. Enoki et al. (115) evaluated the changes in nasal airway resistance and cross-sectional area of nasal cavity in cases with mixed-dentition. They found no significant change in cross- sectional area of nasal cavity although significant decrease occurred in nasal airway resistance.

2.5. Effects of RME on Nasopharyngeal or Respiratory Diseases

Effects of RME on nasopharyngeal or respiratory diseases have been subjected in a few studies. According to our knowledge, first study on this topic published by Gray (76) in 1975. Gray (76) stressed that benefits of orthopedic maxillary expansion should not be limited with the changes only in dental correction, nasal airflow, and mouth breathing, since this treatment procedure has positive effects on respiratory infections, allergic symptoms of respiration, sleeping, eating, speech, naso-central reflexes, and pituitary growth hormone levels. He based his opinions on new medical status of 310 subjects after RME therapy. This author found that over 80% of the cases changed their breathing pattern from mouth to nose and approximately half of the cases could be protected from cold, respiratory infections, nasal allergy, and many cases of asthma. Second article on this issue was published by Brogan (118) in 1977. He carried out an investigation on 516 patients with naso-respiratory problems, and reported that 75% of the cases did not return to otorhinolaryngologist for similar problems until 5 years. Timms (79) reported that rate of improvement in upper airway infections was 82% after RME. Timms (79) summarized respiratory virtues of RME as follows:

1. Widening of nasal airway decreases the airway resistance and this improved natural physiological function reduces respiratory diseases and morbidity. 2. This non-surgical widening method (RME) prevents scar tissue formation, destruction of intranasal morphology, and loss of erectile tissue. 3. RME can also be applied in early time periods when surgery is inadvisable.

92 Nihat KILIÇ and Husamettin OKTAY

Cazzolla et al. (119) investigated the changes in aerobic micro flora of oropharynx on 50 oral breathers suffering from maxillary constriction and posterior cross-bite, aged 8-14 years, and found that Staphylococcus aureus, one of the most common and potentially pathogenic oral microorganisms, reduced in 40% of the patients undergone RME. Based on this result, they suggested that RME may reduce the risk of respiratory infections in oral breathers.

3. Skeletal and Dental Abnormalities and Treatment Options Related with Mandible

The lower jaw, mandible, is subjected to many abnormalities. Mandibular deficiency (retrusion) is very common in general population, but mandibular excess (protrusion) is less common than mandibular deficiency. Class II and III relationships of jaws and teeth are abnormalities in sagittal direction. In these situations, lower jaw and/or lower teeth are positioned more posteriorly or anteriorly relative to upper jaw and/or teeth. Patients with skeletal Class II malocclusions are characterized by a mandibular deficiency, maxillary protrusion, or combination of both. Clinically, these patients may have a retrusive mandible and a protrusive maxilla, causing a convex facial profile.

3.1. Effects of Mandibular Retrusion and/or Deficiency on Pharyngeal Structures

Mandibular retrusion refers to a normal developed but posteriorly located mandible. Mandibular deficiency refers to an underdeveloped mandible which seems as mandibular retrusion. In the subjects with mandibular retrusion and/or deficiency, SNB angle (relating mandible with anterior cranial base) is decreased. Patients with mandibular retrusion may have normal, protrusive, or retrusive maxilla. A close relationship exists between the position and length of mandible and nasopharyngeal structures. During the growth of nasomaxillary complex, forward and downward movement of mandible allows the naso- and oro-pharynx to enlarge to accommodate the increased respiratory functional demands of growing children. Mandibular deficiency has been linked to reduced oro-pharyngeal airway dimensions (Figure 6). Figueroa et al. (120) found that infants with Pierre Robin sequence had a shorter tongue and mandibular length, narrower airway, smaller tongue area, and that the hyoid position was more posterior and inferior as compared to normal infants. Abu Allhaija and Al- Khateeb (121) pointed out that vertical airway length became less in Class II male subjects, and that the position of hyoid bone and the width of inferior pharyngeal space had a significant but weak correlation with the change in anteroposterior skeletal pattern. Kikuchi (122) found that pharyngeal airway volume was influenced by the anteroposterior position of mandibular bone. Similar findings were also reported by Muto et al. (123). However, de Freitas et al. (124) showed that malocclusion type does not influence upper and lower pharyngeal airway widths, and that only the upper pharyngeal width in the subjects with Effects of Maxillofacial Disorders on Pharyngeal Structures... 93

Class I and Class II malocclusions and vertical growth pattern was significantly narrower than those in the normal growth-pattern groups.

Figure 6. Lateral cephalometric head film showing reduced oro-pharyngeal airway dimensions of a subject with mandibular deficiency.

Dunn et al. (10) found no relationship between the variations in ramal height and mandibular length and the variations in nasopharyngeal airway size in monozygotic twins. Ozbek et al. (125) revealed that the subjects with maxillo-mandibular retrusion had the same oro-pharangeal dimensions with normal subjects.

3.2. Effects of Functional Appliances on Pharyngeal Structures

Functional orthopedic appliance therapy objectively aims to create favorable oral and pharyngeal environments by correcting anteroposterior position of mandible. A more favorable dentofacial growth and development is expected to occur after functional orthopedic therapy. Primary clinical objectives of Class II treatment are to correct existing problems in the hard and soft tissues, to correct large over-jet and convex skeletal and soft tissue profile, to improve occlusal function, and to obtain a well-balanced dento-skeletal and neuromuscular relationship (126). Functional orthopedic appliances have been commonly used for the treatment of skeletal Class II malocclusions with mandibular deficiency (Figure 7). These appliances positioned the mandible forward and downward to stimulate or accelerate mandibular growth (126,127). The most commonly used functional appliances are the removable tooth-borne appliances: Activator, bionator, and twin block appliances (127). According to our knowledge, effects of functional orthopedic appliances on pharyngeal structures have been neglected and this issue has been evaluated in limited studies (125,128). Özbek et al. (125) studied the effects of functional-orthopedic treatment on oro-pharyngeal dimensions of growing patients with Class II malocclusion, and concluded that oropharyngeal dimensions increased significantly in treated patients, especially those with sagittally smaller and more retrognathic maxillomandibular complexes and smaller oropharyngeal airway dimensions. In a long-term study, Hänggi et al. (128) evaluated effects of activator-headgear therapy on pharyngeal airway dimensions, and concluded that this 94 Nihat KILIÇ and Husamettin OKTAY combined treatment approach has the potential to increase pharyngeal airway dimensions, such as the smallest distance between the tongue and the posterior pharyngeal wall or the pharyngeal area. According to these authors, this benefit may result in a reduced risk of developing long-term impaired respiratory function.

Figure 7. Functional orthopedic appliance (Activator).

4. Effects of Maxillomandibular Abnormalities on Sleep-Disordered Breathing

Obstructive sleep-disordered breathing is present commonly in children. Complete or partial obstruction of airway during sleep causes loud snoring, oxyhemoglobin desaturation, and frequent arousal, causing unrestful sleep and excessive daytime sleepiness. Snoring, mouth breathing, and obstructive sleep apnea often prompt parents to seek medical attention for their children (129). Three to twelve percent of the children suffer from snoring, while obstructive sleep apnea (OSA) affects 1-10% of the subjects (130-132). The majority of these children have mild symptoms, and many of them outgrow this condition. OSA often results from adenotonsillar hypertrophy, neuromuscular disease, and craniofacial abnormalities. OSA is a common sleep-related breathing disorder characterized by disruptive snoring and the intermittent cessation of breathing during sleep due to the collapse of the pharyngeal airway (133). Rama et al. (134) showed that the primary site of obstruction was at the level of oro-pharynx although extensions to the laryngo-pharynx are frequently observed It has been suggested that transverse maxillary deficiency (maxillary constriction) is one of the possible risk factors for OSA (135,136). OSA patients have high prevalence of maxillary constriction and narrowed maxilla and more tapered and shorter maxillary archers than the normal subjects (135). Cephalometric evaluations showed following two- dimensional deviations from normal morphology:

1. Mandibular retrognathia in children (137) and adults (138). 2. Maxillary and mandibular retrusion (bimaxillary retrusion) in children (139) and adults (140). 3. Lowered hyoid bone position in children (139) and adults (138) Effects of Maxillofacial Disorders on Pharyngeal Structures... 95

4. Increased mandibular plane angle and posterior rotation of mandible in children (141) and adults (142) 5. Increased facial heights in children (141) and adults (140) 6. Extended head posture (143). 7. Reduced dimensions of the pharynx in children (141,144) and adults (140,142). 8. Long soft palate (138) and reduced functional area of the tongue (145). 9. Maxillary constriction in children (135,136) and adults (146).

4.1. Effects of Mandibular Anterior Repositioning Devices on OSA

The idea of using an oral appliance to reduce upper airway obstruction is not new. Pierre Robin described such a concept in children with life-threatening upper airway obstruction related with micrognathie inferior and glossoptosis, well before OSA was even recognized as a disorder. Continuous positive airway pressure (CPAP) is the preferred treatment for sleep apnea (147). Since CPAP requires continuous wearing an obtrusive device during sleep, patients may abandon CPAP therapy. Oral appliances are a simple alternative to continuous positive airway pressure (CPAP) for treating mild to moderate obstructive sleep apnea (OSA), and to intolerance to CPAP treatment (148,149). Oral appliances for the treatment of obstructive sleep apnea (OSA) are worn during sleep to maintain the patency of the upper airway by increasing its dimensions (137), reducing its collapsibility (138), and modifying the position of the mandible, tongue, and pharyngeal structures. Although it has been suggested that oral appliance therapy is effective for sleep apnea, it is generally considered less effective than CPAP (150,151). Oral appliances used for OSA generally divided into two categories: Mandibular anterior repositioning appliances (splints) and tongue-retaining appliances. Mandibular anterior repositioning appliances require the patient to have sufficient teeth, whereas tongue-retaining appliances can be used in edentulous patients since tongue-retaining appliances use suction pressure to maintain the tongue in a protruded position during sleep. Mandibular advancement splints are most commonly used oral appliances. Mandibular anterior repositioning appliances are effective in a substantial proportion of patients with mild to moderate OSA, and lesser proportion of those with severe OSA (152). These appliances are also effective and viable for the treatment of patients with moderate to severe OSA who are intolerant or refuse the treatment with CBAP. Effectiveness of these type appliances decreases with the severity of the sleep apnea and increased obesity (153). Numerous uncontrolled studies have been carried out for evaluation of effectiveness of different types of oral appliances, mainly mandibular anterior repositioning devices, on OSA symptoms. These studies reported varying degree of success ranging from 76 per cent for mild OSA to 40 per cent for more severe OSA (154-158). Randomized and controlled studies (159,160) comparing oral appliances and placebo appliances demonstrated that oral appliance improved apnea-hypnoe index as well as hypoxia in patients with OSA. Long-term studies of mandibular anterior repositioning appliances in the treatment of snoring and sleep apnea suggest a high success rate, with follow-up periods of 2–5 years (155,161,162). According to 96 Nihat KILIÇ and Husamettin OKTAY these studies, about 80 percent of the patients were successfully treated with one-piece oral appliance. It was also reported in these studies that a similar or slightly lesser percentage of patients will also be satisﬁed with the long- term effect on snoring. Liu et al. (163) suggested that a mandibular repositioner might be an effective treatment alternative for obstructive sleep apnea and that a reduction in the frequency of apneic episodes was mainly attributed to the effects of the appliance on oropharyngeal structures.

4.2. Effects of Rapid Maxillary Expansion (RME) Appliances on OSA

The precise role of maxillary constriction in the pathophysiology of obstructive sleep apnea (OSA) is unclear. However, it is well known that the subjects with maxillary constriction have increased nasal resistance and resultant mouth-breathing, features typically seen in OSA patients (135). In orthodontics clinics, RME has been commonly used for expansion of constricted maxillary arches and correction of skeletal and dental cross bites. RME may be also potential or contributory treatment alternative to currently used methods in mild-to-moderate OSA cases with maxillary constriction and posterior cross bite. The rationale for application of RME is present of narrowed maxillary arches requiring skeletal expansion of both maxillary halves. However, possible effects of RME on sleep-disordered breathing and improvement of mild to moderate OSA have been subjected in a few studies (97,98,164,165). Cistulli et al. (97) made first evaluation concerning the effects of RME on OSA in 1998. These authors found that RME produced positive effects in nine out of 10 young patients having mild to moderate OSA and maxillary constriction. Pirelli et al. (98,164), Villa et al. (165), and Rose and Schessl (166) suggested that RME was effective in the treatment of sleep related disorders of growing children with OSA and maxillary constriction. Villa et al. (165) showed that statistically significant decreases occurred in apnea-hypopnea, hypopnea obstructive and arousal indexes of children with OSA and constricted maxilla. Bonetti et al. (167) and Guilleminault and Li (168) found an improvement in cases with maxillomandibular transverse constriction and OSA after maxillomandibular transverse expansion. These authors suggested that maxillomandibular transverse expansion can be useful for treating severe OSA with transverse deficiency. Increased pharyngeal dimensions, new tongue posture, changing of anatomical structures, improved nasal airflow, significant improvements of nasopharyngeal functions, and reduced naso-respiratory problems are considered as possible effective factors for improving of OSA after the expansion. Cistulli et al. (97) speculated that ‗‗the mechanism for the resolution of OSA following RME relates to improved nasal airflow, which results in the generation of lower subatmospheric inspiratory pressures and hence reduces the vulnerability to pharyngeal collapse.‘‘ It seems that RME may produce beneficial effects on patients with maxillary constriction and OSA. However, controlled, randomized, and long term studies are required for make a precise conclusion and obtain evidence based result.

Effects of Maxillofacial Disorders on Pharyngeal Structures... 97

Conclusions

Diagnosis and treatment of the children having maxillofacial disorders, nasal obstruction and long-lasting mouth breathing require a multidisciplinary approach. The pediatrician is usually the first health professional who encounter with that children at earlier age. Pediatricians and otorhinolaryngologists must be familiar with the dental literature regarding dentofacial development and basic concepts of orthodontic intervention in order to provide optimal care for their pediatric patients. Although orthodontic treatment is carried out to correct dental and skeletal discrepancies, treatment outcomes may be effective on pharynx, naso-respiratory problems and OSA of the growing children, especially during pre-pubertal and pubertal growth period. However, it must be keep in mind that, naso-respiratory and pharyngeal aspects of orthodontic interventions were evaluated in limited studies and must be subjected to new studies.

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Chapter IV

Velopharyngeal Dysfunction

1Mosaad Abdel-Aziz, 2Mona Hegazi and 3Hassan Ghandour 1Faculty of Medicine, Cairo University, Egypt. 2, 3Faculty of Medicine, Ain Shams University, Egypt.

Abstract

The velopharyngeal port is the area bounded by the soft palate, the posterior pharyngeal wall and the lateral pharyngeal walls. Insufficient closure of this port will lead to leakage of air during speech (with the acoustic consequence of hypernasality) and leakage of fluids during swallowing (nasal regurgitation); a problem that is called velopharyngeal dysfunction (VPD). Its causes may be congenital or acquired. Overt cleft palate - even after its repair - is the commonest cause. Submucous cleft palate, neuromuscular disorders of the palate, palatal fistula are other causes. Post-operative VPD may occur following adenoidectomy, palatopharyngoplasty for sleep apnea and maxillary advancement. However, the cause may sometimes be unknown. Management of this problem is rather complex and requires a teamwork approach. Members of the team share in primary evaluation, planning of treatment and following up the results of intervention. At least, an otolaryngologist, a phoniatrician/speech language pathologist, and prosthetist should work together during management. Treatment decisions must be based, not only on subjective practitioner‘s impression, but also on data provided by some clinical diagnostic tools, such as nasopharyngoscopy, and videofluoroscopy. The treatment approaches may be non-surgical in the form of speech therapy or prosthetics, and/or surgical in the form of palatal surgery (e.g. Z-plasty or intravelar veloplasty) or pharyngeal surgery (e.g. pharyngoplasty, pharyngeal flap or posterior pharyngeal wall augmentation).

Introduction

The vocal tract, represented by the pharynx, the oral cavity and the nasal cavity, is responsible for the resonating function of the speech mechanism. The velopharyngeal valve, 110 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour consisting of the soft palate (velum), the lateral pharyngeal walls, and the posterior pharyngeal wall, is critically important for normal speech production because it is responsible for regulating the transmission of sound energy between the oral and nasal cavities. This valve is also important in swallowing preventing food and fluid regurgitation through the nose. Velopharyngeal dysfunction (VPD) is the general term describing the condition where the velum and lateral and posterior pharyngeal walls fail to separate the oral cavity from the nasal cavity during speech and deglutition. It is used to describe different disorders of the velopharyngeal valve, including velopharyngeal insufficiency (VPI), referring to anatomical causes, and velopharyngeal incompetence, referring to physiological defects [1]. VPD results in articulatory problems and hypernasal speech which is unintelligible and less pleasant causing a negative impact on the social life of the patient. Children with hypernasal speech are often considered less intelligent, less pleasant, and less attractive. Such perceptions can seriously affect the social life of children.

Functional Anatomy

Velopharyngeal closure (at the level of the first cervical vertebra), is primarily a sphincteric mechanism consisting of a velar component and a pharyngeal component. During function, the velum moves in a superior and posterior direction until it makes firm contact with the posterior pharyngeal wall. Movement of the velar component is produced principally by the action of the levator veli palatini muscle. The velum must be of sufficient length, to span the entire depth of the pharynx like a ―veil‖ or ―curtain‖. At the same time, the lateral pharyngeal walls move medially to either close against the velum, or in some individuals, behind the velum. Movement of the pharyngeal component, if it occurs, is more dependent on the contraction of the superior constrictor and the palatopharyngeal muscles. The coordinated movement of these muscles and the rest of the palatine muscles results in complete closure of the valve at appropriate times for normal speech [1, 2, 3]. The following paired muscles (Figure 1) are important components of the velopharyngeal valve:

- The tensor veli palatini: It arises from the scaphoid fossa, spine of the sphenoid, and the cartilaginous portion of the eustachian tube. It inserts into a tendon winding around the hamular process to reach the hard palate. Its main function is to make the soft palate tense supporting the action of other muscles. It also opens the eustachian tube during swallowing. It is innervated by the mandibular branch of cranial nerve V [4]. - The levator veli palatini: It arises from the petrous apex and cartilaginous portion of the eustachian tube. Its fibers fan out in the soft palate and blend with the contralateral levator forming a sling; so it is the major elevator of the velum. It is innervated by the pharyngeal plexus from cranial nerves IX and X [5,6,7]. Velopharyngeal Dysfunction 111

- The musculus uvulae: It arises from the palatal aponeurosis posterior to the hard palate and it inserts into the uvular mucosa. It adds bulk to the dorsal aspect of the uvula. It is innervated by the pharyngeal plexus [4,8].

Figure 1. Schematic illustration of the muscles of the soft palate seen from behind. TP, Tensor veli palatini. LP, Levator veli palatini. MU, Musculus uvulae. PP, Palatopharyngeus. PG, Palatoglossus. PH, pterygoid hamulus. HP, Hard palate. C, Choana.

- The palatopharyngeus: It arises from the soft palate and inserts into the posterior border of the thyroid cartilage. It narrows the velopharyngeal orifice by adducting the posterior pillars and constricting the pharyngeal isthmus. It also stretches the velum laterally increasing the area of contact between the palate and the pharyngeal wall. - The palatoglossus: It arises from the anterior surface of the soft palate and inserts into the lateral aspect of the tongue base, it simultaneously lowers the velum and elevates the tongue upwards and backwards. Both the palatoglossus and the palatopharyngeus muscles have opposing action to the levator veli palatini muscle. They are innervated by the pharyngeal plexus [9-13]. - The superior constrictor: It arises from the lower portion of the pterygoid plate and the hamular process and inserts into the median raphe. It produces medial movement of the lateral pharyngeal walls and assists in drawing the velum posteriorly. Passavant‘s ridge, seen in some individuals during swallowing and speech, is believed to be caused by forward movement of the uppermost fibers of the superior constrictor. It is also believed to be involved in velopharyngeal closure in some individuals. The superior constrictor is innervated by the pharyngeal plexus [6,7,13,14].

For many years, it was assumed that the velopharyngeal valve worked the same way for all normal individuals. In the early 1970s and 1980s, studies showed that there was significant variability in the method that normals used to achieve closure of the velopharyngeal port. Croft et al [15] and Siegel-Sadewitz and Shprintzen [16] found that 112 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour during velopharyngeal closure, normals used variable degrees of (a) posterior movement of the velum, (b) lateral pharyngeal wall motion toward the midline, and (c) posterior pharyngeal wall motion. The variations in the contribution of each of these components produce the several patterns of velopharyngeal closure. Skolnick et al [14] introduced four categories of velopharyngeal valving that differentiate the method of velopharyngeal closure (Figure 2). These velopharyngeal closure patterns are:

1. Coronal pattern. Velopharyngeal closure is accomplished mainly by posterior movement of the velum toward the back of the pharynx with relatively little lateral pharyngeal wall motion and no posterior pharyngeal wall motion. 2. Sagittal pattern. Velopharyngeal closure is accomplished primarily by lateral pharyngeal wall movement toward the midline with relatively little contribution from movement of the velum. The lateral pharyngeal walls often move to midline and approximate each other. The posterior pharyngeal wall is not active. 3. Circular pattern. Velopharyngeal closure involves equal contribution of posterior movement of the velum and movement of the lateral pharyngeal walls towards the midline. There is no posterior pharyngeal wall movement. In this pattern, the midline bulge of the musculus uvulae becomes the target for the medial movements of the lateral pharyngeal walls. 4. Circular with Passavant's ridge pattern. This pattern is essentially the same as the circular pattern (contribution of the velum and lateral pharyngeal walls to velopharyngeal closure), except that there is also movement or bulging of the posterior pharyngeal wall (Passavant's ridge).

Figure 2. Illustration of endoscopic view for different velopharyngeal closure pattern at rest, during partial and complete closure. A, Coronal closure; B, Sagittal closure; C, Circular closure; D, Circular closure with Passavant‘s ridge. Velopharyngeal Dysfunction 113

Witzel and Posnick [17] performed a detailed study of the patterns of velopharyngeal closure on patients with VPI. Two-thirds (67%) of the patients had typical closure patterns that were easily categorized using the four velopharyngeal closure patterns previously described. The most common pattern of closure -that was found- was the coronal pattern (68% of the typical group). Less common patterns were the circular pattern (23% of the typical group) followed by the circular with a Passavant's ridge pattern (5%), and the sagittal pattern (4%). The remaining one-third of the patients (33%) had patterns that were considered atypical (i.e. they cannot be described by any of the preceding patterns). Based on Witzel and Posnick's [17] findings, the following atypical patterns may be encountered:

1. Presence of asymmetrical valving. This refers to significant differences between the ability to achieve closure of one side relative to the other side. 2. Presence of a deep midline indentation of the velum. When velopharyngeal closure is attempted, the lateral portions of the velum achieve adequate closure. However, air escapes through the midline indentation of the superior surface of the velum. 3. Presence of a prominent bulge of the midline of the velum. When velopharyngeal closure is attempted, the midline bulge of the superior surface of the velum achieves closure. Air escapes from both sides of the lateral aspects of the velum. An upward flip or protrusion of the uvula may occur with this pattern. 4. Presence of a midline indentation of the adenoid tissue. The velum comes in contact with the posterior pharyngeal wall achieving closure only at the lateral aspects while air escapes through the midline indentation. 5. Presence of a prominent midline bulge of the adenoid tissue. Closure of the velum is achieved against the midline adenoid bulge, but air escapes through the lateral aspects.

Etiology

VP1 can occur for a variety of reasons with classification based on its etiology. Categories of classification are structural abnormalities of the palate; dynamic impairment of a structurally normal palate; and functional abnormalities unassociated with anatomic or dynamic palatal defects. To date, the true incidence of the categories of VP1 etiology is unknown. The majority of the studies have reported most VP1 cases to be in the structural category [18].

- Overt cleft palate is the most common cause, even after palatoplasty. The frequency of hypernasality after cleft palate repair that may need secondary surgery varies in different literatures between 15-45% [19]. This wide range of incidence is due to the presence of different techniques for repair of cleft palate and even every technique is not universally done by different surgeons. Of all these techniques, the Furlow palatoplasty becomes the most common procedure for cleft palate closure [20]. 114 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour

- A submucous cleft palate is defined by the presence of a bifid or double uvula, muscular diastasis of the soft palate (zona pellucida), and notching of the posterior border of the hard palate [21]. The structural presentation of submucous cleft palate indicates that the levator palati muscles have been shifted from their normal transverse orientation to a longitudinal position [22]. This is usually evident on examination of the oral cavity, especially with elevation of the palate when pronouncing the phoneme /ah/. - Occult submucosal cleft palate is an absence or deficiency of the musculus uvulae with a diastasis of the levator veli palatini but without the presence of a bifid uvula or grooving of the oral surface of the soft palate [23]. An occult submucous cleft is best visualized endoscopically as the absence of the bulge on the nasal surface of the soft palate during speech [24]. - Post-adenoidectomy VPI may be transient due to post-operative pain that results in spasm of palatal and pharyngeal muscles [25], but sometimes the condition is persistent and it needs surgical intervention. A large adenoid can compensate for a short or a poorly mobile palate; with adenoidectomy the mechanism of compensation is eliminated [4], also occult submucos cleft overlooked during the pre- adenoidectomy assessment may be the cause [23]. When persistent postadenoidectomy VPI occurs in a patient with anatomically normal palate, an underlying chromosomal abnormality may shed light on the occurrence of this unusual problem i.e. deletion of 22q11 [26]. - Post-palatopharyngoplasty: A procedure that used for the treatment of snoring and sleep apnea; in which part of the redundant soft palate is removed can sometimes lead to VPI [27]. - Post-maxillary advancement: Maxillofacial surgeons use this approach for the treatment of maxillary hypoplasia, many of them reported a deleterious effect of the procedure on the speech and velopharyngeal function [28]. - Mechanical impairment of palatal elevation caused by tonsillar hypertrophy has been reported to cause VPI [2,29]. - Muscular hypotonia may cause VPI as seen in velocardiofacial syndrome, Kabuki syndrome, Down syndrome, myasthenia gravis and multiple neurofibromatosis [4,30].

Velopharyngeal incompetence secondary to a neurogenic deficit may be congenital, although it is most often acquired [18,31]. The disturbance in speech production is caused by a weakness, paralysis, or a lack of coordination of speech musculature. The injury may be localized to cranial nerves IX, X, or XI, lower motor nerves, upper motor nerves, and/or the cerebellum. The localization and severity of the impairment will dictate whether speech intelligibility will improve with velopharyngeal valve remediation. Velopharyngeal incompetence may also be a feature of other syndromes (eg, neurofibromatosis, myotonic dystrophy). Acquired VPD may present in persons affected by stroke or head injury, especially if damage occurs to motor centers controlling cranial nerves responsible for pharyngeal muscle control. Other neurologic diseases (eg, muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease) also may lead to VPD in the more advanced stages of the disease. Articulation problems and VPD are especially common in patients undergoing pallidotomy for severe Parkinson disease. Velopharyngeal Dysfunction 115

Functional forms of VPD occur for a variety of reasons in the absence of any organic cause. These include faulty speech habits (mostly due to imitation), mental retardation, hearing impairment and in post-adenoidectomy pain. However, misarticulations may present in a manner similar to that seen in velopharyngeal incompetence [32]. Phoneme-specific misarticulations refer to the occurrence of nasal emission on certain pressure consonants in the absence of any hypernasal resonance. Fricatives (s, z) and affricates (ts, dz) are most vulnerable to this type of misarticulation. These conditions should not be misdiagnosed as velopharyngeal incompetence.

Communicative Problems

A. Effects on Speech

VPI can affect speech in a variety of ways, depending on the size of the opening and the cause. Common characteristics include: hypernasality, nasal air emission, weak or omitted consonants, short utterance length, and obligatory and compensatory articulation productions.

1. Hypernasality Hypernasality is an excessive nasal resonance during vowel production - often associated with - but not the same as nasal escape of air. It is due to oral-nasal coupling within the vocal tract that is sufficient to result in a perceptually significant change in the speech sound [33].

2. Nasal air emission It is the passive escape of air into the nasal cavity and out the nose. Nasal emission occurs when there is an attempt to build up intraoral air pressure for the production of consonants in the presence of a leak through the velopharyngeal valve (or an oronasal fistula). Nasal emission is most noted on pressure-sensitive phonemes (plosives, fricatives, and affricates). It does not occur during the production of vowels or semivowels because these sounds do not require a build-up of air pressure. Nasal emission often occurs with hypernasality, but can also occur with normal resonance. If nasal emission is absent in the presence of VPI, this indicates nasal obstruction. Nasal emission can be very soft and barely audible (can only be seen with a mirror), or it can be very loud and distracting. This has to do with the size of the velopharyngeal gap. When there is a large gap, there is little resistance to flow. Although there is significant loss of air pressure through the nose, the nasal emission is not audible due to the minimal resistance. With a smaller gap, the nasal airflow is more audible because there is more resistance. Very small velopharyngeal openings can actually cause more speech distortion than those that are bigger. This is because air that is forced through a small or narrow opening creates significant pressure. As it is released on the nasal side of the opening, this causes bubbling of the nasal secretions, which is very audible. The speech distortion that occurs as a result of the bubbling is called a nasal rustle (or nasal turbulence). A nasal rustle can be very loud and distracting and can mask the sound of the consonant, thus affecting both the intelligibility and quality of speech. It usually occurs on the voiced pressure consonants 116 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour

/b/, /d/, and /g/ [1, 34]. When air passes through the velopharyngeal valve or an oronasal fistula, it reduces the amount of air pressure that is available in the oral cavity for the production of consonants. This causes the consonants to be weak in intensity and pressure, or causes them to be omitted completely. The greater the nasal emission, the weaker the oral consonants will be [35].

3. Obligatory and compensatory speech errors A distinction between obligatory errors and compensatory errors is important to make because the compensatory characteristics are under the patient‘s control and can therefore be modified with speech remediation (preferably after the structure is corrected).

I. Obligatory errors These are purely a direct consequence of anatomic or physiologic defects such as VPI or malocclusion. They do not respond to speech therapy (which is even contraindicated). They are spontaneously corrected after correction of the cause [36, 37]. Besides nasal air emission, nasal turbulence and weak oral consonants may be found. Nasal turbulence (nasal rustle) is a noisy nasal emission that passes an obstruction as deviated septum or congestion. It usually occurs in bursts with pressure consonants production (stops, fricatives, affricates). Weak oral consonants (stops, fricatives, affricates) due to reduced intraoral pressure. This occurs due to VPI, large anterior fistula and attempt to reduce nasal emission [38].

II. Compensatory errors 1. Compensatory adaptations

These are errors which are the speaker's closest possible approximation to a target sound in the presence of anatomic deviations. They are close to or exactly like the target sound, although they look incorrect. They may or may not resolve spontaneously after correcting the anatomic deviation, thus they may need speech therapy to correct them afterwards. Teaching these compensations may be needed sometimes to enhance speech intelligibility. Examples include:

(a) articulatory inversion: in severe class III malocclusion there may be upside down /f/ and /v/. (b) Usage of different articulators: as in severely protruding maxilla there may be labiodental /p/, /b/, /m/ neglecting the upper lip.

2. Compensatory articulation errors

These are unconscious mechanism by which the individual tries to make up for fancied or real deficiencies. They are '' maladaptive compensatory errors" that do not work in terms of producing good speech although they may work in terms of constricting the air stream. Examples are:

Velopharyngeal Dysfunction 117

a. Glottal stops that replace plosives, typically back plosives, but may involve also any other consonants. b. Nasal snort which is an error produced when the speaker forces air out the nose usually during sibilants or fricatives. c. Posterior nasal fricative (velar or velopharyngeal fricative) that is produced due to constriction between the velum and posterior pharyngeal wall. d. Pharyngeal fricative which is produced by constriction of the vocal tract or constriction between the retracted tongue and pharynx to create frication. e. Mid-dorsal palatal stop where the tongue blade contacts the palate in a central region anterior to /k/, /g/ and posterior to /t/, /d/. The boundary between /k/ and /t/ is lost this occurs more with anterior fistula, and less with VPI. f. Laryngeal fricatives produced by frication at the level of the larynx usually to substitute a fricative [38, 39, 40].

Speech related behaviours such as nasal grimace or the severer facial grimace usually accompany VPI [41] and are trials from the patient to obstruct the outgoing nasal airflow at a final station. The obligatory and compensatory articulation errors ultimately reduce the degree of speech intelligibility of subjects with VPD. The effect of these errors on speech intelligibility is more paramount than when hypernaslity is present alone without the errors.

B. Effects on Voice

A common phonatory disorder is that of reduced loudness. Children will often use reduced vocal volume in an attempt to decrease nasal resonance and nasal emission. Compensatory glottal articulation may eventually lead to hyperfunctional dysphonia, and vocal nodules may develop [42, 43]. However, a more recent study by Hamming et al [44] showed no relationship between VPI and dysphonia. They proved that the overall rate of dysphonia in a population with cleft palate was within the reported range for the normal population of children.

Assessment of Velopharyngeal Insufficiency

Hirschberg [45] mentioned that ―the adequate assessment of the various forms of VPI can only be solved successfully with multidisciplinary co-operation. Since, however, the concomitant functional disorders belong first of all to the competency of the otolaryngologist and phoniatrician, the contribution of the representatives of these two disciplines in the teamwork and care is indisputable‖. According to Karnell and Seaver [46], assessment of velopharyngeal function has achieved four goals: to assess structure, movement, extent of closure, and timing of closure. These findings are to be correlated with the perceptual judgment of the patient‘s speech. When surgical treatment is indicated, further investigation using a visualization technique is usually the next step. The visualization methods are coupled with information extracted from 118 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour other tools that may give more objective or quasi-objective values about the velopharyngeal functions. The protocol validated by Kotby et al [47] suggests three levels of assessment according to the complexity of the tools used. The first level consists of elementary diagnostic procedures that are rather simple, non-invasive but essentially subjective. Despite the clinical feasibility of these procedures, an attempt to objectify the data is made utilizing the tools on the second level of assessment, namely, the clinical diagnostic aids. The third level of assessment, namely, additional instrumentation measures, uses a more sophisticated armamentarium of research tools in an attempt to quantify the qualitative, quasi-objective measures deduced from the clinical diagnostic aids: The elementary diagnostic measures include patient and parent interview, auditory perceptual assessment (APA) of the patient‘s speech, visual perceptual evaluation (examination) of the vocal and oral tract and simple clinical tests for the detection of the presence and degree of hypernasality.

The patient and parent interview describes personal data, parent consanguinity, any similar conditions in the family, complaint, prenatal, perinatal and postnatal history, developmental milestones, time of discovery of the problem by the family, and history of speech problems. It also describes history of nasal regurge, presence of any other anomalies, detailed history of operative intervention (type, age and place of surgery), any otological complaints, as well as subjective parents‘ impression of hearing, swallowing, intellectual abilities [48].

The auditory perceptual assessment (APA) of the patient‘s language, speech and voice is done by listening to the patient‘s utterance or recorded speech sample. If the patient is a child, a detailed comment on language is done. Passive and active aspects are investigated including semantic, syntactic and pragmatic aspects. Speech assessment is done by commenting on the degree and type of nasality, consonant precision, compensatory articulatory mechanisms, audible nasal emission of air, facial grimace and overall intelligibility of speech. All of the above elements are graded along a 5-point scale starting with 0 (normal) to 4 (severely affected) [47].

The visual perceptual assessment includes assessment of face (for asymmetry and facial anomalies), lips (for fullness, mobility, closure and scars), maxilla (protruded or retruded), teeth (for anomalies), tongue (for size, symmetry and mobility), tonsils (present or absent, and size) as well as the tonsillar pillars. The hard palate is assessed to describe clefts, scars, and/or fistulae. The soft palate is evaluated at rest and during movement (voluntary and reflex) to comment on the length and amount of mobility. The uvula is also described. Signs of submucous cleft (are searched for by inspection and palpation). The lateral and posterior pharyngeal walls mobility is assessed. The nose (nasal septum and shape of alae) and ears (tympanic membrane and middle ear effusion) are assessed [49]. The intraoral examination provides limited information about palate structure and function. Many important findings can be missed, including the exact extent and level of palatal elevation, malformation of the Velopharyngeal Dysfunction 119 musculus uvulae, occult submucous cleft palate, and adequacy of velopharyngeal valving [11]. Simple clinical tests that indicate the adequacy of the velopharyngeal function. They include Czermak‘s cold mirror test [50] and Gutzman‘s (/a/, /i/) test [51]. Czermak‘s cold mirror test demonstrates and detects nasal air escape. It is done by putting a cold mirror in front of one of the patient‘s nares during the production of prolonged vowels (/a/, /i/) and prolonged fricatives (s-sh-f). The test is considered positive if air is condensed on the cold mirror. The Gutzman‘s (a/i) test is done by closing and opening the nares alternately by gentle pressure while the patient is uttering alternately a i. In case of VPI, there will be a difference in the nasal resonance between occluded and unoccluded utterance, so the test is positive [52]. The clinical diagnostic aids comprise documentation of both the APA and documented visualization of the velopharyngeal port. It also comprises different formal testing for language, speech and psychometric evaluation. Audiological testing is also performed. Documentation of APA is done using high fidelity speech and voice audio-recording. According to Shprintzen [53], diagnostic procedures designed to visualize the velopharyngeal mechanism should be able to determine the following characteristics of VPI to guide subsequent treatment: (a) the size of the gap, (b) the location of the gap, (c) the shape of the gap, (d) the consistency or inconsistency of the gap, and (e) the component movements of the velum, lateral pharyngeal walls, and posterior pharyngeal wall. Although radiographic analysis has commonly been used to evaluate VPI, one of the best methods to observe the velopharyngeal valve directly and to assess these characteristics is with the use of nasal endoscopy [54, 55].

The fiberoptic "flexible" nasopharyngolaryngoscope is provided with a high intensity cold light and a special endoscopic television system for videotape recording. Nasofiberoscopy does not only allow direct observation of the anatomy and the dynamic activity of the velopharyngeal sphincter but also allows the patient to observe his own velar function, so it can be used as a therapeutic tool during speech therapy as the patient can control the desired action visually. During nasopharyngolaryngoscopy, the movements of lateral and posterior pharyngeal walls are observed. Movement of the soft palate during respiration and different speech tasks are evaluated. The pattern of velopharyngeal closure is described. Central velar gaps, the supralaryngeal compartments and the vocal folds are assessed.

Radiological studies include still radiography, cineradiography, CT scan, multiview videofluoroscopy (MVF), magnetic resonance imaging (MRI) and X-ray microbeam. Still radiography uses dead lateral exposures during rest and during sustained a vowel. It measures the palatal length and elevation as well as the pharyngeal depth. Cineradiography achieves a dynamic assessment of velum, posterior and lateral pharyngeal wall movements during connected speech. CT scan [47, 56] assesses mobility of velum, lateral and posterior pharyngeal walls, but it needs a cooperative patient (> 5 years). Its advantages are the easy definition of measured parameters, the provision of automated numerical values regarding the size of the velopharyngeal gap and the amount of displacement of each wall as well as the 120 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour provision of information about the vertical level of closure of the velopharyngeal port referring to surrounding structures. On the other hand, it gives no information about the dynamic function during speech production. The effect of gravity in the supine position may alter the actual picture of velar function. Moreover the amount of exposure to radiation cannot be overlooked. The multiview videofluoroscopy (MVF) has gained a wide acceptance as a reliable tool for the diagnosis of VPI. Videofluoroscopy is the most used radiographic method in the investigation of velopharyngeal function, since the radiation dosage is one tenth that of cinefluorography [57]. The barium instilled through the nose coats the surface of the velum and posterior pharyngeal wall, allowing visualization of all structures in all dimensions (width, depth, and height). However, the problems with overlapping shadows and asymmetry on velopharyngeal function can complicate the interpretation of these studies [58]. Some of these problems may be overcome by the multiple views of the technique. The Lateral view (Figure 3) describes the length and thickness of the velum, the extent of its movement towards the posterior pharyngeal wall, the presence and size of adenoid pad, the presence of Passavant's ridge. It also describes tongue movement during speech and the velar height during closure in relation to hard palate. The Frontal (AP) view describes the extent of the medial movement of the lateral pharyngeal walls, symmetry of their movement and may allows description of the approximate level of maximum movement of the lateral pharyngeal walls. The oblique views (right and left) permit observation of the interaction between the lateral pharyngeal wall and edge of the velum on each side. These views help to define the source of velar asymmetry. Base view can detect problems with closure. In addition to describing lateral pharyngeal walls and velar movements, the closure pattern of the velopharyngeal port is readily visualized. The Modified Towne's view shows the port from above. It is an alternative to the base view. It may be a better view if adenoids are large that causes change of the angulation of closure within the nasopharynx. This view can detect the same parameters described in the base view.

Figure 3. Lateral videofluoroscopic view for a patient with VPI; A, at rest and B, during phonation of sustained /a/. The arrow points to the velum and the arrow head points to the posterior pharyngeal wall [58]. Velopharyngeal Dysfunction 121

MVF may be preferred to CT in assessment of the velopharyngeal function because of the advantages of the reduction in total radiation dosage and the ability to assess in real time the motion of the velopharyngeal port during sustained phonation and connected speech.

MRI offers potential advantage over naso-endoscopy in being non-invasive and over videofluoroscopy in avoiding radiation. However, it requires costly equipment and patient cooperation, which limits its use in young patients. MRI is a useful investigation that permits visualization and measurement of velopharyngeal changes at rest and during phonation in all possible axes, with better resolution than fluoroscopy. However, its use is limited in uncooperative children. Any intraoral metalwork for dental problems restricts its use for palatal investigation. The cost involved in installing an MRI machine restricts its availability in each hospital [59]. Formal testing includes performing detailed language and articulation tests as well as psychometric tests for determining the mental age. Different tests are used according to the patient‘s age, associated auditory or motor problems. A full audiological evaluation should be performed for patients with VPI because of the very high incidence of Eustachian tube dysfunction frequently accompanying VPI. The additional instrumental measures include acoustic, aerodynamic and electromyographic studies. Other investigations such as genetic studies and velar biopsy are performed when indicated. The Nasometer is the most widely used method for acoustic analysis of speech in VPI (Figure 4). Nasometry was developed by Fletcher and Bishop in 1970 [60]. Since then, it has established a firm position as a diagnostic tool [61]. Nasometry is a quick, non-invasive and objective procedure [62], and because of its widespread use in many countries, it allows multi-centre comparison of data. The nasometer provides the user with a "nasalance score" which is a numeric ratio that reflects the relative amount of nasal acoustic energy in the subject‘s speech. A study by Mishima et al [63] indicated that nasalance scores correlate the ratio of the velar length to the pharyngeal depth and to the amount of velar ascent during blowing.

Figure 4. A patient during nasometric assessment of his speech.

122 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour

The aerodynamic studies of velopharyngeal port depend on the patency of the nasal cavities and the nasal airflow regulation by the palatal movement. Thus the degree of the velopharyngeal closure can be determined from the extent of the nasal airflow or relative distribution of the air pressure rate in the oral nasal tracts. The nasal airflow can be monitored by a pneumatography. Warren et al [64] pointed out that nasal airflow rates above 150 ml/S during non-nasal consonant production may indicate VPI. Nasal airflows under 150 ml/S do not necessarily indicate adequate velopharyngeal function, because a speaker with gross VPI can produce low nasal airflow when there is nasal obstruction. The intranasal pressure also may reflect the degree of velopharyngeal gap. Calculating nasal flow and oral pressure at the same time greatly reflects the function of the velopharyngeal valve. The intraoral air pressure is the force tending to drive air through the port, while the nasal airflow represents the failure of the velopharyngeal port to withstand that pressure. The simultaneous recording of both provides a good illustration of the effectiveness of velar closure. Normally, stop consonants are characterized by a relatively high intraoral pressure and very little nasal airflow. An incompetent velopharyngeal valve often causes a severe reduction of the pressure and a great increase in the transnasal flow. Warren [65] recommended using the difference between intraoral and intranasal pressure during production of /p/ sound as an index of palatal efficiency. A special computer interfaced and software-controlled instrument, the Palatal Efficiency Rating Computed Instantaneously (PERCI) has been designed to facilitate differential pressure measurement. The instrument (PERCI) is formed of 3 transducers. The first transducer for oral pressure, the second transducer for nasal pressure and the third transducer for nasal flow. The three transducers are connected to the Speech Aerodynamic Research System (SARS) unit using a single connector. The system is connected to a microcomputer and a Windows program, which automatically calculate oral pressure, nasal pressure, nasal airflow and velopharyngeal orifice area when the patient utters the sample word in request (Figure 5). The velopharyngeal orifice area is calculated using the following equation:

A = V/k (2 P/d)½

Where A = area of velopharyngeal orifice, V = nasal airflow, k = 0.65, P = oral-nasal pressure and d = density of air.

Warren et al [64] described the following values for velopharyngeal orifice: adequate closure (<5mm2 gap), borderline adequate (5-9.9mm2), borderline inadequate (10 - 19.9 mm2), and inadequate closure (20 mm2 or more).

Velopharyngeal Dysfunction 123

Figure 5. The PERCI-SARS system.

Electromyography (EMG) provides basic information about muscle activity during speech [66]. This is done using bipolar hooked wire electrodes inserted into velopharyngeal musculature. This technique is considered invasive and painful. Besides, the precise placement of electrodes is rather difficult. EMG may diagnose neurogenic cause of VPI. It also detects electrically silent tissue to help its surgical excision.

Treatment

1. Interdisciplinary Team

The management of VPD requires a team that includes an otolaryngologist, a plastic surgeon, a phoniatrician, a logopedist, an audiologist, an orthodontist, a clinical psychologist, a geneticist, radiologist and a pediatrician. Members of the team share in primary evaluation, planning of treatment and following up the results of intervention.

2. Non-Surgical Treatment

A. Speech therapy Speech therapy improves velopharyngeal function when the dysfunction is minimal and in postoperative patients where functional residual VPI is present. Compensatory articulation errors secondary to VPD also can be corrected with speech therapy. Hypernasality or variable resonance due to oral-motor dysfunction (dysarthria or apraxia) can be corrected by speech therapy. However, in patients with a specific anatomic deficiency that prevents adequate closure of the velopharynx, speech therapy cannot replace surgery. The general goals of articulation therapy is to teach the correct direction of air stream, to teach the correct articulation of all consonants and vowels, establish a good coordination of velopharyngeal closure with other articulatory muscles, and then to introduce the newly 124 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour learned sounds into connected speech. The articulation therapy should always avoid forceful production of speech sounds. Regardless of the nature of errors produced, multiple types of cues may be provided to elicit production of sounds [67]. These cues are:

1. Auditory cues: where the patient repeats a sound or word produced by the clinician. 2. Phonetic cues: a sound produced correctly is used as a phonetic facilitator to elicit another sound using a series of successive approximations. 3. Manual cues: the therapist (or the patient) manipulates the lips, tongue or nose of the patient. Example is the use of clenching the nares to force oral air emission during sibilant and fricative production. 4. Tactile cues: touch is used to provide the patient with feedback about some aspects of production, such as asking the child to feel oral breath stream of /f/. The child is asked to lightly touch the side of his/her nose to feel for vibration during the production of nasal phonemes versus oral phonemes. Then the child is asked to carefully produce oral sounds or sentences without the vibration. 5. Visual cues: the patient watches the therapist while using his articulators directly or in a mirror to provide visual feedback. Several devices are available to assist with this method. Simple tools (eg, cold mirror, paper paddle) can serve to show the patient when nasal escape occurs. Other devices are commercially available, such as the See-Scape, which is placed at the nose and causes a ball to rise when airflow is nasal rather than oral. Nasopharyngoscopy has been used to achieve visual feedback [68]. The Nasometer, which graphically displays a ratio of oral sound energy to nasal sound energy, is also used in this respect. The visual readout can help the therapist and patient develop compensatory techniques to reduce nasalance.

It has been observed that hypernaslity is sometimes reduced indirectly after articulation therapy. Though the articulation therapy does not aim at changing velopharyngeal motion but this is a benefit that is sometimes observed [69]. During articulatory training, slowing the rate of speech, using greater mouth opening and light articulatory placement to reduce expiratory effort, are all techniques that aid reduction of hypernaslity. All feedback techniques also help in managing hypernasality.

B. Prosthodontic treatment Prosthetic intervention with a soft palate obturator or speech aid prosthesis is done in children with VPI who are not surgical candidates for soft palate reconstruction (due to systemic, anatomical, functional, or social disturbances), or who have had less than optimal surgical results. Obturators can substitute for tissue deficiency and are attached to the teeth by metal wire or bands [70]. In certain cases, the obturator can be downsized gradually so that the native tissue, if adequate in bulk, can strengthen over time and compensate for the decreasing obturator size. A palatal lift appliance (PLA) is used in neurogenic VPI. The lift prosthesis is designed to improve velopharyngeal closure by elevating the neuromuscularly incompetent soft palate to the palatal plane level to enable the pharyngeal walls to make easier valving contact. It is Velopharyngeal Dysfunction 125 hoped that the degree of lift can be reduced gradually until the appliance can be discarded. Unfortunately, in many instances the prosthesis must be worn indefinitely [71]. If the length of the soft palate is insufficient to induce closure after maximal displacement with the palatal lift appliance, the addition of an obturator component may be necessary. This adjustment may be required for patients with bulbar lesions. The use of a PLA, however, is still controversial [72].

3. Surgical Management

The primary indications for surgical intervention include a structural defect of the velum or a functional problem that results in poor or inconsistent velar closure. Maximum benefit can be achieved when surgical technique takes advantage of whatever native velopharyngeal function exists in the patient. Information obtained during evaluation via physical examination, nasopharyngoscopy, and/or MVF greatly aids in determining how to accomplish the maximum benefit in the best way. Determination of a patient's predominant velopharyngeal closure pattern usually directs the surgeon to the most appropriate surgical procedure for the patient. Surgical options are to repair palatal clefts, palatal fistulas, or to improve the function of the velopharyngeal sphincter in the absence of clefts or fistulas. However, treatment of cleft palate and palatal fistulas were not considered in this chapter. Methods to improve the velopharyngeal function are many and they can be divided into 2 types; palatal procedures and pharyngeal procedures. The aim of the palatal procedures is to improve the palatal muscles function through reorientation of the levator veli palatini. The technique used is either Furlow Z-palatoplasty or intravelar veloplasty. The aim of the pharyngeal procedures is to narrow the velopharynx by sphincter pharyngoplasty, pharyngeal flap, or posterior wall augmentation. The choice between different methods depends on the data provided by the preoperative evaluation, and the most important factor that directs the surgeon to the best beneficial method is the type of velopharyngeal closure pattern [73]. All these procedures are done under general anesthesia with oral endotracheal intubation. The Dingman mouth gag is used to maintain the mouth opened and the sites of the incisions are injected with small amount of 0.5% Xylocaine with epinephrine 1:200,000 to achieve local hemostasis. Then the surgeon proceeds according to the selected technique that has been already designed preoperatively.

Furlow Z-palatoplasty It was first described by Furlow in 1986 [74]. It is done as a primary procedure to repair cleft soft palate, submucous cleft palate or as a secondary procedure to lengthen a repaired short palate. The technique is started with midline division of the palate if it was intact. For right handed-surgeon, it is easier to start with elevation of the myomucosal flap of the left side of the palate that is based posteriorly and is formed of oral mucosa and muscle layer leaving about 2 mm posterior to hard palate to facilitate closure. Care should be taken not to injure the thin nasal mucosa; which is created as a left nasal mucosal flap by incising it near the posterior edge of the soft palate. The oral mucosa is elevated from the muscle layer on the right side of the palate so that the mucosal flap is based anteriorly with the incision has been 126 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour made just anterior to the posterior edge of the soft palate. The right myomucosal flap is then created by incising the muscle layer and nasal mucosa about 2 mm behind the posterior edge of the right side of the hard palate. This left cuff of tissue could facilitate closure (Figure 6). Now, four flaps have been created; two myomucosal flaps based posteriorly and two mucosal flaps based anteriorly. The left nasal mucosal flap is rotated across the midline to be sutured to the right hard palate margin and the right nasal myomucosal flap is then rotated to the left to be inserted into the left hemi-palate. The contact line between both flaps is sutured. At this stage the nasal layer of the soft palate is established and is formed of anterior nasal mucosal flap and posterior nasal myomucosal flap. The right oral mucosal flap is rotated across the midline to be sutured to left hard palate margin and the left myomucosal flap is then rotated to the right and sutured to the posterior soft palatal edge. The contact line between both flaps is then sutured. Now the oral layer has been developed and is formed of anterior oral mucosal flap and posterior oral myomucosal flap. The uvula is re-approximated and sutured.

Intravelar veloplasty It can be done either as a secondary procedure in post-palatoplasty VPI when the levator sling had not been created in the primary operation or included in the initial palatal repair. Its principle depends on re-orientation of the levtor veli palatini muscle [75]. The edges of the cleft are incised to separate the oral from the nasal mucosa, elevation of the oral mucoperosteum from the hard palate, the procedure proceeded to elevation of oral mucosa exposing the palatal muscles which are inserted to the posterior border of the hard palate. The muscles are then freed from their abnormal insertion with careful dissection to avoid injury of the thin nasal mucosa. Complete freeing of muscles from oral and nasal mucosa is essential. The muscle fibers are then directed medially towards each other and closed with mattress sutures after closure of nasal mucosa (Figure 7). Fracturing the pterygoid hamulus may facilitate approximation of the muscles. The uvula is re-approximated and the oral mucosa is closed. Although, the operation reconstructs the normal horizontal orientation of the levator, the results are not necessarily satisfactory [76].

Figure 6. Furlow palatoplasty; A, creation of the four flaps and B, after closure. LO, Left oral myomucosal flap; LN, Left nasal mucosal flap; RO, Right oral mucosal flap; RN, Right nasal myomucosal flap. Velopharyngeal Dysfunction 127

Figure 7. Intravelar veloplasty; A, The levators are postioned vertically where they are attached to the posterior border of the hard palate and B, The levators are transposed horizontally and sutured together.

Pharyngeal flap Schoenborn first reported this procedure in 1876. It was the operation of choice for many years. Although it is used as a secondary procedure after cleft palate repair, some surgeons used it primarily for correction of VPI as in cases of submucous cleft palate [22]. It can be designed either superiorly based (Figures 8, 9) or inferiorly based. However, most surgeons prefer the former one [77] as the latter pulls the palate downwards rather than upwards. It is created by elevation of myomucosal flap from the posterior pharyngeal wall (superior constrictor muscle and its overlying mucosa) to be inserted into the soft palate either in its free posterior border between oral and nasal surfaces (fish-mouth technique) or midway between posterior end of hard palate and posterior end of soft palate after palatal split [78]. The width of the flap can be decided according to the velopharyngeal gap seen by the preoperative flexible nasopharyngoscopy [22]. Two rubber catheters should be introduced from the nose to the hypopharynx before elevation of the flap, a point that maintain 2 lateral gutters reducing the postoperative obstructive problems. Now, the velopharynx becomes divided into 2 lateral ports by the flap that bridges the central part and the lateral pharyngeal walls close against it during articulation of non-nasal consonants. It is ideal for patients with preoperative sagittal closure pattern with some evidence that the lateral wall motion will improve after the operation [79]. However, complications may include hyponasality, nasal obstruction, snoring and even sleep apnea [4,80].

Sphincter pharyngoplasty Hynes was the first to describe pharyngoplasty in 1950 [81]. It is now the operation of choice by most surgeons because it has low risk of airway obstructive problems and it is suitable for patients with preoperative coronal and circular closure pattern that constitute a high percentage of cases [4,82]. It is created by elevation of bilateral myomucosal flaps from the posterior tonsillar pillars and lateral pharyngeal walls (Figure 10) (palatopharyngeus and the lateral part of posterior constrictor muscles and their overlying mucosa) [83] which are sutured together and are inserted into an incision on the posterior pharyngeal wall [84]. The 128 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour two lateral flaps are sutured together in end-to-end fashion or may overlap each other. It can be done through retraction of the soft palate by 2 rubber catheters, or for better visualization, the soft palate may be sectioned in the midline. Some surgeons reported that velar motion may be increased after the procedure [12]. Sphincter pharyngoplasty appears to be a more ―physiologic‖ solution, as it intends to preserve the circumferential nature of the muscles and their contribution to velopharyngeal closure.

Figure 8. Pharyngeal flap inserted into the middle part of the soft palate.

Figure 9. The marked area is the site of incision for elevation of the superiorly based pharyngeal flap.

Velopharyngeal Dysfunction 129

Figure 10. Sphincter pharyngoplasty. A, The marked area is the site for incisions; B, The bilateral palatopharyngeal flaps elevated with a horizontal incision in-between; C, End-to-end anastomosis of the flaps with closure of the donor sites.

Posterior pharyngeal wall augmentation This approach may be appropriate in patients with minimal velpharyngeal gap. A superiorly based pharyngeal flap incorporating the superior constrictor is raised down to the prevertebral fascia. The superior extent of elevation is defined just above the point of maximal closure seen in the preoperative nasopharyngoscopic assessment. It then is buckled onto itself and sutured in place [85] (Figure 11). Initially, good results can be obtained, but later on, the flap may atrophy. Both autogenous tissue and foreign implants have been used for this approach. Fat has also been used [86], but it may be reabsorbed with time. Silicone and Teflon are no longer used due to their extrusion effect. Recently, calcium hydroxyapetite has been used but the data were obtained from small sample of patients [87].

Figure 11. Posterior pharyngeal wall augmentation. 130 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour

Conclusion

Management of velopharyngeal insufficiency needs co-operation between members of a team that shares in the diagnosis and treatment of this problem. This teamwork should include at least an otolaryngologist, a phoniatrician/speech language pathologist and a prosthetist. The management decisions must be based, not only on the subjective practitioner‘s impression, but also on the data provided by the clinical diagnostic tools such as nasopharyngoscopy, videofluoroscopy. The treatment approaches may be non-surgical in the form of speech therapy or prosthetics, and/or surgical in the form of palatal surgery (e.g. Z-plasty or intravelar veloplasty) or pharyngeal surgery (e.g. pharyngoplasty, pharyngeal flap or posterior pharyngeal wall augmentation).

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[31] Minami, RT; Kaplan, EN; Wu, G; Jobe, PR. Velopharyngeal incompetence without overt cleft palate. A collective review and experience with 98 patients. Plast Reconstr Surg, 1975, 55, 573-587. [32] Johns, D; Tebbettsm, JB; Cannitom, M. Perceptual-acoustic analysis: the self-lined, pull- through pharyngeal flap. In: A. G. Huddart, & M. J. W. Ferguson, (Eds.), Cleft Lip and Palate, the Older Patient and Future Prospectives. ND: Manchester University Press; 1990, 69-83. [33] Curtis, JF. Acoustics of speech production and nasalization. In: D. C. Spriesterbach, & D. Sherman (Eds.O), Cleft Palate and Communication. New York: Academic Press; 1968, 326-330. [34] Wyatt, R; Sell, D; Russell, J; Harding, A; Harland, K; Albery, E. Cleft palate speech dissected: a review of current knowledge and analysis. Br J Plast Surg, 1996, 49(3), 143-149. [35] Kummer, AW. Resonance disorders and nasal emission: Evaluation and treatment using low tech and ―no tech procedures. Asha Leader, 2006, 11(4), 4-26. [36] Philips, BJ; Kent RD. Acoustic-phonetic description of speech productions in speakers with cleft palate and other velopharyngeal disorders. In: N. Lass, editor. Speech and Language: Advances in Basic Research and Practice. New York: Academic Press; 1984, 113-167. [37] Sell, DA; Harding, A; Grunwell, P. A screening assessment of cleft palate speech (Great Ormond Street Speech Assessment). Eur J Disord Commun, 1994, 29, 1-5. [38] Golding-Kushner, K. Treatment of articulation and resonance disorders associated with cleft palate and VPI. In: R. Shprintzen, & J. Bardach, (Eds.), Cleft palate speech management: A multidisciplinary approach. St. Louis, MO: Mosby; 1995, 327-351. [39] Trost, JE. Articulatory additions to the classical description of the speech of persons with cleft palate. Cleft Palate J, 1981, 18, 193-203. [40] Trost-Cardamone, JE. Diagnosis of specific cleft palate speech error patterns for planning remediation of physical management needs. In: K. R. Bzoch, editor. Communicative Disorders Related to Cleft Lip and Palate (Vol. 4). Austin, TX: Pro- Ed; 1997, 313-330. [41] Sell, D; Ma, L. A model of practice for the management of velopharyngeal dysfunction. Br J of Oral & Maxillofacial Surg, 1996, 34, 357-363. [42] Hocevar-Boltezar, I; Jarc, A; Kozelj, V. Ear, nose, and voice problems in children with orofacial clefts. J Laryngol Otol, 2006, 120, 276-281. [43] Kasten, E; Schmidt, S; Zickler, C; Berner, E; Damian, L; Christian, GM; Workman, H; Freeman, M; Farley, M; Hicks, T. Team Care of the Patient with Cleft Lip and Palate. Current Problems in Pediatric and Adolescent Health Care, 2008, 38(5), 138-158. [44] Hamming, KK; Finkelstein, M; Sidman, JD; Minneapolis, MN. Hoarseness in children with cleft palate. Otolaryngology–Head and Neck Surgery, 2009 in press. doi:10.1016/j.otohns.2009.01.036. [45] Hirschberg, J. Models of management of velopharyngeal valve incompetence in developing countries. Tasks of the otolaryngologist and phoniatrician in multidisciplinary care. International Congress Series, 2003, 1240, 677-682. Velopharyngeal Dysfunction 133

[46] Karnell, MP; Seaver, E. Measurement problems in estimating velopharyngeal function. In: J. Bardach, & H. L. Morris (Eds.). Multidisciplinary Management of Cleft Lip and Palate. Philadelphia: WB Saunders; 1990, 776-86. [47] Kotby, MN; Abdel-Haleem, EK; Hegazi, M; Safe, I; Zaki, M. Aspects of assessment and management of velopharyngeal dysfunction in developing countries. Folia Phoniatrica et Logopedica, 1997, 49, 139-146. [48] Abdel-Haleem, EK. Protocol of assessment of velopharyngeal incompetence. Proceedings of the XVII World Congress of the International Federation of Oto-Rhino- Laryngological Societies (IFOS). International Congress Series, 2003, 1240, 663-667. [49] Finkelstein, Y; Hauben, DJ; Talmi, YP; Nachmani, A; Zohar, Y. Occult and overt submucus cleft palate: From peroral examination to nasoendoscopy and back again. International Journal of Pediatric Otorhinolaryngology, 1992, 23(1), 25-34. [50] Czermak JN. Gesammelte Schriften. Vienna, vol 1. In: R. Luchsinger, & G. E. Arnold, (Eds.), Voice, Speech and Language. London: Constable; 1965, 668. [51] Gutzmann, H. Ein Mass für die Nasalität. Arch Neen Physiol, 1922, 7, 321. [52] Moller, KT. An approach to the evaluation of velopharyngeal adequacy for speech. Clinics in Communication Disorders, 1991, 1(1), 61-65. [53] Shprintzen, RJ. The implications of the diagnosis of Robin sequence. Cleft Palate Craniofac J, 1992, 29, 205-209. [54] Ibuki, K; Karnell, MP; Morris, HL. Reliability of the nasopharyngeal fiberscope (NPF) for assessing velopharyngeal function. Cleft Palate J, 1983, 20(2), 97-107. [55] Finkelstein, Y; Lerner, MA; Ophir, D; Nachmani, A; Hauben, DJ; Zohar, Y. Nasopharyngeal profile and velopharyngeal valve mechanism. Plastic and Reconstructive Surgery, 1993, 92(4), 603-614. [56] Honjo, I; Mitoma, T; Ushiro, K; Kawano, M. Evaluation of velopharyngeal closure by C.T. scan and endoscopy. Plast Reconstr Surg, 1984, 74(5), 620-627. [57] Isberg, A; Julin, P; Kraepelien, T; Henrikson CO. Absorbed doses and energy imparted from radiographic examination of velopharyngeal function during speech. Cleft Palate J, 1989, 26, 105-109. [58] Abou-Elsaad, T; Hegazi, M; Zaki, M; Amer, A. Videofluoroscopic assessment of velopharyngeal port. Presented in the annual meeting of the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF), Toronto, Canada, September 17-20. Journal of Otolaryngology-head and Neck Surgery, 2006, Vol. 135 (2) (Supplement), 118. [59] Vadodaria, S; Goodacre, TEE; Anslow, P. Does MRI contribute to the investigation of palatal function? British Journal of Plastic Surgery, 2000, 53(3), 191-199. [60] Fletcher, SG; Bishop, ME. Measurement of nasality with Tonar. Cleft Palate J, 1970, 7, 610-621. [61] Dalston, RM; Warren, DW; Dalston, ET. Use of nasometry as a diagnostic tool for identifying patients with velopharyngeal impairment. Cleft Palate Craniofac J, 1991, 28, 184-188. [62] Hirschberg, J; Bo´k, S; Juha´sz, M; Trenovszki, Z; Votisky, P; Hirschberg, A. Adaptation of nasometry to Hungarian language and experiences with its clinical application. Int J Pediatr Otorhinolaryngol, 2006, 70, 785-798. 134 Mosaad Abdel-Aziz, Mona Hegazi and Hassan Ghandour

[63] Mishima, K; Yamada, T; Sugii, A; Hideto, I; Toshio, S. Relationships between nasalance scores and nasopharyngeal shapes in cleft palate patients. Journal of Cranio- Maxillofacial Surgery, 2008, 36(1), 11-14. [64] Warren, DW; Dalston, RM; Morr, K; Hairfield, W. The speech regulating system. Temporal and aerodynamic responses to velopharyngeal inadequacy. Journal of Speech and Hearing Research, 1989, 32, 566-575. [65] Warren, DW. Perci: A method for rating palatal efficiency. Cleft Palate Journal, 1979, 16(3), 279-285. [66] Sonoda, T. Study of Velopharyngeal Movement in Cleft Palate Patients Following Pharyngeal Flap Surgery. Journal of Japanese Cleft Palate Association, 2001, 26(1), 68-87. [67] Kummer, AW; Lee, L. Evaluation and treatment of resonance disorders. Language, Speech, and Hearing Services in Schools, 1996, 27, 271-281. [68] Ysunza, A; Pamplona, M; Femat, T; Mayer, I; García-Velasco, M. Videonasopharyngoscopy as an instrument for visual biofeedback during speech in cleft palate patients. Int J Pediatr Otorhinolaryngol, 1996, 41(3), 291-298. [69] Golding-Kushner, KJ. Therapy techniques for cleft palate speech and related disorders. San Diego, CA: Singular Publishing; 2001. [70] Gallagher, B. Prosthesis in velopharyngeal insufficiency: Effect on nasal resonance. Journal of Communication Disorders, 1982, 15(6), 469-473. [71] Wolfaardt, JF; Wilson, FB; Rochet, A; McPhee, L. An appliance based approach to the management of palatopharyngeal incompetency: a clinical pilot project. J Prosthet Dent, 1993, 609, 186-195. [72] Reisberg, DJ. Dental and prosthodontic care for patients with cleft or craniofacial conditions. Cleft Palate Craniofac J, 2000, 37, 534-537. [73] Ysunza, A; Pamplona, MC; Ramírez, E; Molina, F; Mendoza, M; Silva, A. Velopharyngeal Surgery: A Prospective Randomized Study of Pharyngeal Flaps and Sphincter Pharyngoplasties. Plast. Reconstr. Surg., 2002, 110, 1401-1407. [74] Furlow, LT Jr. Cleft palate repair by double opposing Z-plasty. Plast Reconstr Surg, 1986, 78(6), 724-738. [75] Krien, OB. Fundamental anatomic findings for an intravelar veloplasty. Cleft Palate J, 1970, 7, 27-36. [76] Marsh, JL; Grames, LM; Holtman, B. Intravelar veloplasty: a prospective study. Cleft Palate J, 1989, 26(1), 46-50. [77] Meek, MF; Coert, JH; Hofer, SO; Goorhuis-Brouwer, SM; Nicolai, JP. Short-term and long-term results of speech improvement after surgery for velopharyngeal insufficiency with pharyngeal flap in patients younger and older than 6 years: 10-year experience. Ann Plast Surg, 2003, 50(1), 13-17. [78] Peat, BG; Albery, EH; Jones, K; Pigott; RW. Tailoring velopharyngeal surgery: the influence of etiology and type of operation. Plast Reconstr Surg, 1994, 93, 948 - 953. [79] Karling, J; Henningsson, G; Larson, O; Isberg, A. Adaptation of pharyngeal wall adduction after pharyngeal flap surgery. Cleft Palate Craniofac J, 1999, 36,166-172. [80] Sloan, GM. Posterior Pharyngeal Flap and Sphincter Pharyngoplasty: The State of the Art. Cleft Palate Craniofac J, 2000, 37(2), 112-122. Velopharyngeal Dysfunction 135

[81] Hynes, W. Pharyngoplasty by muscle transplantation. Br J Plast Surg, 1950, 3, 128-131. [82] Sie, KC; Tampakopoulou, DA; de Serres, LM; Gruss, JS; Eblen, LE; Yonick, T. Sphincter pharyngoplasty: speech outcome and complications. Laryngoscope, 1998, 108, 1211-1217. [83] Abdel-Aziz, M. Palatopharyngeal sling: A new technique in treatment of velopharyngeal insufficiency. Int J Pediatr Otorhinolaryngol, 2008, 72, 173-177. [84] Orticochea, M. A review of 236 cleft palate patients treated with dynamic muscle sphincter. Plast Reconstr Surg, 1983, 71, 180-186. [85] Gray, SD. Pinborough-Zimmerman, J; Catten, M. Posterior wall augmentation for treatment of velopharyngeal insufficiency. Otolaryngol Head Neck Surg, 1999, 121, 107-112. [86] Dejonchere, PH; van Wijngaarden, HA. Retropharyngeal autologous fat transplantation for congenital short palate: a nasometric assessment of functional results. Ann Otol Rhinol Laryngol, 2001, 110(2), 168-172. [87] Sipp, JA; Ashland, J; Hartnick, CJ. Injection pharyngoplasty with calcium hydroxyapetite for treatment of velopalatal insufficiency. Arch Otolaryngol Heah Neck Surg, 2008, 134(3), 268-271.

Chapter V

Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology

*Carmen Aurelia Mogoanta$, *Elena Ionita and**Mogoanta Laurentiu *ENT Department, University of Medicine and Pharmacy of Craiova. **Histological and Immunohistochemical Research Center of the Medicine University of Craiova, 2-4 Petru Rareş Street, 200349 Craiova, România,

Waldayer‘s lymphatic ring represents an anatomo-physiological defense structure localized at the gate of both the digestive and respiratory system, with two major roles – reducing the amount of germs that can enter the body and a tampon role between the immune system and different antigens, ensuring a normal and correct differentiation of the B and T lymphocytes. The ring is composed of 6 more or less individualised anatomic structures – 2 palatine tonsils, 2 tubal tonsils, 1 pharyngeal tonsil (Luschka), and a tonsil at the base of the tongue – and a variable amount of disseminated interposed lymphoid follicles. All the lymphoid structures of Waldayer‘s ring have similar architecture. They are constituted from a covering epithelial tissue which sends infoldings to the underlying stroma, forming the crypts, surrounded by lymphoid follicles disposed in lobules, separated by lax connective tissue. The epithelium is keratinised – malpighian type excepting the pharyngeal tonsil who has a respiratory pseudo-stratified epithelium [12]. The amigdalian crypts are deep and narrow in palatine and pharyngeal tonsils and superficial in lingual and tubal tonsils. This particular aspect makes the palatine and pharyngeal tonsils more susceptible to inflammations explained by stasis of the pathogens at the cryptic level. Amigdalian cryptic epithelium also named lymphoepithelium due to the increased number of lymphocytes contained into it plays a significant role in the immune response initiation at the amigdalian level as, the luminal antigens from the crypts are taken over and presented to some specialized cells localized at the level of the amigdalian epithelium [16]. In some cases at the level of tonsils covering epithelium, we observed relatively frequent erosions, leading to a direct contact of the

$ Corresponding author: Phone: +40728-020623, E-mail: [email protected] 138 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu amigdalian follicles to the saprophyte or pathogenic flora present in the pharynx. We consider that the erosions of the surface epithelium are the effect of aggressive pathogenic agents [10]. Using electronic microscopy techniques, some authors observed discontinuities just like fissure, at the level of the amigdalian epithelium, especially at the level of the tonsilary crypts. Surface epithelium hurting enables gates for the pathogenic agents to enter which explains the recurrence of the amigdalian inflammatory processes, turning the tonsils into hotbed diseases, thus forming a vicious chain that can be solved only by the tonsillectomy [4, 28]. The lymphoid follicles represent the highest structural organization form of the lymphocyte population disposed in a specific cytofibrillary stroma. In the structure of lymphoid follicles we can distinguish the central zone formed by lymphoblasts and young lymphocytes and the cortical zone occupied by mature lymphocytes, macrophages, dendritic cells and plasmocytes. The architecture of the follicles is easily understood in dynamics – the lymphocytes become mature and differentiated along their way from the center of the follicle to the surface where they are specialized in the contact with specific antigens. The interfolliculary areas are mainly populated by T lymphocytes [10]. Amygdalian chorion is well represented; it consists of lax conjuctive tissue and numerous lymphocytes and lymphoid follicles. Two types of lymphoid follicles can be found into the tonsils structures, such as:

- primary lymphoid follicles - secondary lymphoid follicles

Clear germinative centre, also called reactive center or clear Fleming centre appears as clearer and less cell loaded on the histologic preparations. In fact, the secondary follicle center is occupied by many lymphoblasts, young cells of larger sizes than the mature lymphocytes, with a large and hypochrome nucleus (due to the lax chromatin disposition). Many lymphoblasts can be surprised during mitosis (the reason for their ―germinative centre‖ name) (Figure 11). Prolymphocytes, rare mature lymphocytes, macrophages, plasmocytes and many dendritic cells can be found among lymphoblasts. Lymphoblasts in the follicle centre, also called ―centroblasts‖ are B lymphoblasts stimulated by an antigene (reactive lymphoblasts). By their multiplication, B antigenic- dependent lymphocytes were formed and would work out specific antibodies for the antigen which had stimulated them. Lymphoblasts are medial sized cells of about 15-18 µm diameter. Nucleus is large and occupies almost all the cell volume. It is eurochromatin riched and presents 1-2 prominent nucleols. Cantitatively-reduced cytoplasma (nucleus/cytoplasma ratio is 6/1) is basophilic with a few cell organelles (excepting the well-developed ribosomes and endoplasmatic reticulum) and it containes nonspecific azurophile granulations. Prolymphocites form as following the lymphoblast division and differentiation processes. They are a little less-sized cells than the lymphoblasts, of 8-15µm diameter and nucleus/cytoplasma ratio is 4/1. Nucleus is dense with just one nucleolus covered by the heterochromatin. Cytoplasma is intensely basophilic. Prolymphocytes would differentiate without division, into lymphocytes. Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 139

Lymphocytes are complete differentiate but yet functionally immature cells. They pass through the follicular crown where they keep on their antigene-dependent maturation. Cortical region or the follicle crown is made up of a dense B mature lymphocytes population which gives a dark aspect to that area, due to its hyperchrome nucleus. Rare lymphoblasts (some of which just in mitosis), plasmocytes and dendritic cells can be found among lymphocytes. Secondary follicles appear as a response to a prolonged antigenic stimulation; they can decrease to primary follicles when antigenic stimulation is absent. Following some prolonged antigenic stimuli, follicles hypertrophy and their diameter is 2-3mm (now they are called ―reactive follicles‖). Lymphoid follicle is not limitted by its own conjuctive structure (capsule) at the periphery; that‘s why the cortical region periphery cannot be exactly delimitted. They are made up of B lymphocytes originating into the clear germinative centre and they grow functionally mature into the cortical layer. Yet, T lymphocytes can be also found at the follicle pole and into the perifollicular lymphocytary infiltrate [10, 30] (Figure 6, 8). In Drinker‘s and Joffrey‘s opinion, lymphatic tissue has got five functions, such as:

- lymphocytes production; - fat metabolism and transport; - vitamins storing; - internal secretions working out; - diseased cells destroying.

Th. C. Lesson‘s and C. Roland Lesson consider that the most important plays of the lymphatic tissues are the following:

- lymphocytes production; - filtration function; - antibodies working out function.

Amygdalian lymphatic ring has mainly an immunologic role intervening both in the humoral mediated response and in the cellular one. Waldayer‘s ring lymphoid formations play a filter part among the bactericide, with a lipoidic character substances; they enrich lympha with fibrinogen and protheolytic diastasis analogous to tripsin [13]. So, the main roles of the lymphatic structures are:

- lymphocytes production - filtration - antibody production.

We can now clearly state that an organism with those functions altered can not defend itself efficiently. Performing tonsillectomy, even if it‘s a minor surgical gesture, and the most frequent surgical interventions in many areas, need a very well documented case study, because we can leave our patients without proper defense in front of aggressive germs for a longer or shorter period of time. 140 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

The pathology of the Waldayer‘s lymphatic ring comes mainly from its role. In the first years of life the contact between the environmental antigens and the body often produces lymphatic structures hypertrophy as a modulated normal reaction but also inflammation which, in some cases, can be considered in the limits of normality. Inflammation exacerbation, even if an acute one, or chronic, or recurrent, is considered pathological and it is treated by diverse means including antibiotics and surgery. The limit between normal and pathological is still unclear and even if the indications for surgery (Table 1) or antibiotics are well stated there is an extremely variable clinical interpretations among the physicians. Very often the patients get to the otolaryngologists after a few empiric treatment attempts that modified the natural evolution of the illness.

Table 1. Indications for surgical management of tonsilary disease [8].

Obstruction Infection Neoplasia Tonsilary hyperplasia with Recurrent/chronic tonsillitis on any suspicion obstruction Breathing disorders Persistent tonsillitis Swallowing abnormalities Tonsillitis with: Abscessed cervical nodes Acute airway obstruction Speech abnormalities Tonsillolithiasis Orofacial/dental abnormalities Streptococcal carrier state unresponsive to medical treatment Lymphoproliferative disorder Cardiac valve disease (after excluding other causes) Peritonsillar abscess unresponsive to medical treatment

In such cases the physical exam becomes less helpful than the data related by the patient or family. We think that in doubtful cases the lack of the medical records should be compensated by serial examination and close survey of the patient. The main indications for surgery are recurrent or chronic infections, obstructive hyperplasia, acute infections with abscess, and of course, tonsilary neoplasia. According to the oropharynx obstructive syndrome, five palatine tonsils hypertrophy degrees were described:

- 0 degree- intravelic tonsils, - I degree –slightly hypertrophied tonsils, 25% reducing the air flow, - II degree- medial amigdalian hypertrophy, 25%-50% reducing the air flow, - III degree- increased amigdalian hypertrophy, 50%-75% reducing the air flow, - IV degree- huge amigdalian hypertrophy, achieving more than 75% air flow reduction [1].

Chronic tonsillitis represent the most frequent lesions within pharynx inflammatory pathology and the most frequent surgically treated of the child, with multiple complications both local-regional (acute median otitis, catarrhal otitis, fibro-adhesive otitis, supurative otitis with hypoacusis, chronic muco-pruritus rhinitis, sinusitis, occular and lacrimalpathways Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 141 infections, descending respiratory infections) and at the distance( glomerulonephritis, joint rheumatism, endocarditis, enteritis, appendicitis, persistent albuminureas etc.) Chronic tonsillitis can be also the location of some specific infections such as: tuberculosis and syphilitic but also maligned lesions. The treatment choice depends also on the age of the patient. It is not advisable to perform tonsillectomy in young patient if we do not have solid data to sustain its necessity. In cases of airway obstruction by tonsils hyperplasia in young patients, tonsilotomy or unilateral tonsillectomy is to be considered against bilateral tonsillectomy. In such cases it is advisable to perform hystopathological exam in order to continue the treatment in the most appropriate way [2, 14]. The inadequate use of the antibiotics represents also a major problem. Without any doubt the antibiotics are useful in acute tonsillitis but using them for long term treatment even in the presence of an antibiogram is not only ineffective but also harmful. This point of view is generally accepted and especially proved by some studies on bacterial resistance developed in amigdalian crypts. The presence of the bacterial biofilms in crypts, in tonsilary inflammations, explains antibiotic resistance and justify why some acute tonsillitis get chronic and recurrent [11, 15, 36]. Other authors consider that the chronic presence of some germ or germs associations, including fungus, determine granulomatous tonsils inflammation, microhemmoragies, that can only be proved by hysto-pathological exam (Figure 4, 5 ). This kind of inflammation imposes tonsillectomy, but the HP exam is too expensive to be used on a large scale [3].

Figure 1. Hypertrophy of the tonsillar follicles with enhanced growth of the germinating clear centre. Haematoxylin-eosin x 400.

142 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

Figure 2. Lymphatic parenchyma from a palatine tonsil with chronic inflammation process. We remark the hypertrophy and hyperplasia of the lymphatic tissue ―dissected‖ by rich collagen fibrosis. Light green Goldner-Szeckeli x 400.

Figure 3. Fibrous tissue tracts developed in the palatine tonsil as a result of recurrent inflammation Light green Goldner-Szeckeli x 1000.

Figure 4. Microhaemorhagic foci in a palatine tonsil. This aspect was frequently observed in the stroma as well as in the parenchyma of the tonsils. Light green Goldner-Szeckeli x 100.

Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 143

Figure 5. Micro- haemorrhage in the tonsillar stroma. Light green Goldner-Szeckeli x 400.

In our opinion the Waldayer‘s ring pathology is more complex that it seems at the first sight and every patient needs special attention before we can establish the therapeutical management of his\her illness. Following this statement we started a few projects with the aim to correlate the clinical aspects with histology and immunohistochemistry, methods that can help us to better understand this pathology. So, pharynx chronic inflammation reveals the endless fight among different external pathogenic agents and Waldeyer‘s ring lymphoid formations which, by the repetitive absorbtion and microbian destruction processes taking place at that level, leads to the pharynx lymphoid tissue hyperplasia [26]. Anatomoclinically, hyperplasias and pharynx non-specific chronic inflammations can be classified such as:

Diffuse chronic pharyngitis as: catarrhal chronic pharyngitis, hypertrophic chronic pharyngitis, congestive chronic pharynopathy, atrophic chronic pharyngitis; Chronic epipharyngitis; Pharynx ozena; Pharyngo-keratosis; Chronic adenoiditis; Inflatmmatory pathology of lymphoid residuals in adult; Chronic tonsillitis; Palatine tonsils hypertrophy; Lingual tonsil hypertrophy; Gerlach‘s tonsil hypertrophy [31].

Pharynx chronic inflammation may be diffuse or localized, according to the inflammatory process degree and area. 144 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

1. Diffuse Chronic Pharyngitis

It represents the diffuse inflammation from the pharynx level and belongs to a more general process including the upper airways (nasal and sinusal suppuration) or lower airways ( laryngo-tracheo-bronchic diseases) [38] ; it is characterized by a mucus hypersecretion as a consequence of the slow disease from the level of the lymphoid structures diffusely distributed on the surface of the pharynx mucosa. Therefore, pharynx mucosa is secondary affected by ethyologic factors from the level of the respiratory tract or other systems, or by general favouring causes, or by environment ones. Rarely, pharyngitis stands for a primary inflammation of the pharingian structures. Among the causal factors, nasal and sinusal suppurations are situated on the first place. Pus and other nasal secretions drainage on the pharynx posterior wall allows a pharynx mucosa chronic inflammation condition. More than that, dental and amigdalian diseases (chronic amigdalitis), all the affections determining nasal obstruction leading to oral noxious breathing (adenoids, septum deviations, hypertrophic chronic rhinitis, nasal polyposis ) [5] may constitute causal factors of diffuse chronic pharyngitis. Conditions leading to pharynx permanent irritation can be added: excessive use of voice (vocal overworking), alcohool abuse, spices, tobacco, environment pollution ( micro- and macroclimate with tobacco, dust, powder noxious vapours) [31]. Lung diseases such as: bronchitis, bronchiectasias, lung drainages can fester the pharynx by septic spittle that reached the pharynx by expectoration; also the digestive disorders (dyspepsias, gastritis) leading to chronic congestive phenomenon at the pharynx level [31]. Other infections such as: liver failure, diabetes, avitaminosis , exudative and lymphatic diathesis improve pharyngian chronic inflammation . Chronic pharyngitis symptomatology is polymorphous. Patients evince dryness sensations, smarting and itching neck leading to spastic caught without expectoration but with intense pharyngeal irritation (permanent neck curage to get rid of secretions). Other symptoms such as: obstructed deglutition, ―neck node‖ or foreign body sensation). All those manifestations are more evident in the morning when the patient is waking and the ―neck cleaning‖ must be done [31]. All along the day it‘s possible that the phenomena should grow calm, getting more and more intense towards the evening, as a consequence of bearing many favoring irritating factors such as : vocal tiredness, smoking, polluted atmosphere . Clinical exam differentiates more anatomoclinical forms of chronic pharyngitis, such as :

Chronic catarrhal pharyngitis: in fact it is an adenopharyngitis and it is characterized by oropharynx diffuse congestion or by a vascular thickness drawing on the posterior wall mucosa covered by viscous mucous secretions [31]. Hypertrophic chronic pharingitis comes in turn or it may be simultaneous to a catarrhal pharingitis ; it is an adenopharyngitis, too; it is produced and kept up by lymphoid follicles chronic inflammations from rhinopharynx. Under that situation, mucopurulent secretion stagnation, for a long period of time, on the cavum mucosa surface, can first lead to a hypertrophy of the lymphoid structures and the subjacent muscle layer, diminishing rhinopharynx sizes and keeping on that pathology. It presents under a granulous form where the hyperplasic lymphoid elements looking Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 145

like small prominences have been disseminated the posterior wall as a lateral pharyngitis or fals posterior pillars , which is secondary to the surgical ablation of palatine tonsils, too, where lymphoid tissue appears as longitudinal cards situated behind the palatal pharyngeal muscle (anterior pillars), giving the impression of their doubling; the rest of the pharyngian mucosa was intensely congestioned , bright red , which was diffusely observed on the palatine vault, palatal and glosseal pharyngeal muscles (anterior and posterior pillars), uvula or palatine tonsils [31]. Atrophic chronic pharyngitis: appears due to the mucosa progressive and mucous and serous glands atrophy following viral or microbian repeated chronic inflammatory processes. If the pharynx mucosa is congestioned for a long time, after the atrophic process, pharyingian posterior wall mucosa becomes pale, dried with a pergamentous matted aspect, sometimes covered with small adherent yellowish crust, finally leading to the organ enlargement. Frequently it is associated to atrophic rhinitis. Dried pharyngitis may be frequently met in old people, like a process of senescence or a final stage of a congestive or hypertrophic catarrhal pharyngitis; it also occurs in patients with TBC, in persons diagnosed with ozena and in some children after adenotonsilectomy. Treatment consists of oily nasal instilments, nasopharynx irrigations with physiologic serum or salty solutions, A vitamin, crenotherapy with sulphurous water [22, 31]. Congestive chronic pharyngopath is met in cardio-vascular, arthritic, diabetic, tobaccic, hepatitic, pletoric patients and it is characterized by a permanent congestion of the pharynx mucosa without mucous or mucopurulent secretions producing [31]. ENT clinically exam reveals an uniform congestion of the pharynx without debut functional symptoms, in evolution adding a spastic dry cough , sometimes disphony , thurst or itching sensations ; chronic irritate and congested mucosa becomes sensitive to sudden temperature and microclimate changes, moment when mucopurulent secretions can appear.

Treatment imposes a pharyngeal hygiene meaning that he/she has to swallow repeatedly , to avoid pharyngeal irritation , vocal rest. To make the local sensations grow calm , patients need saline solutions , emollient inhalations , iodate glycerin buffer ( when catarrhal pharyngitis) with light solution of silver nitrate in hyperthrophic pharyngitis or vitamin A oily solution or iodate glycerin in atrophic pharyngitis. The way to administrate drugs as to get the pharynx is the nasal instilments, inhalations, pulverizations, aerosols. Those therapeutic procedures are used in the balneoclimateric resorts, with sulphurous waters, for the catarrhal pharyngitis and with iodate waters in atrophic pharyngitis (the so called crenotherapy). Also are used for the treatment heliomarine cure or climatetherapy and body strengthening by sports. Having into account numerous factors determining pharyngitis , their suppression is imperative necessary.

146 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

Chronic Epipharyngitis

Cavum mucosa chronic inflammation which expresses by a drying sensation behind the palatine vault appears due to nasal- sinusal repeated inflammations as a consequence of respiratory type epithelium existence, at cavum level, thus explaining the stronger reactions against external microbian aggression, as well. Mucous or mucopurulent secretions join the mucosa and become dried during the night subduing the patient to a coughing effort to eliminate them. By evaluating, chronic inflammation extends to Eustachio tube leading to chronic tubal-tympanic catarrh with transmission hipoacusia [38]. Chronic epipharyngitis evolution occurs in three stages; the first catarrhal stage, in posterior rhinoscopy the mucosa appears as congested and covered with mucopurulent secretions lowering down the rhinopharynx posterior wall. In the second stage, mucosa is thickened, hypertrophied also interested in Eustachio‘s tube pharyngeal orifice mucosa finally leading to cavum diminishing. When rhinopharyngeal touching is performed, at that stage, one can feel his/her finger pressed by the upper constrictor muscle contraction. The last stage is of an atrophy , frequently met in old people and the former is characterized by the presence of a pale, thinned mucosa covered with dried crusts not so bad smelled as those in ozena [31]. Rhinitis and atrophic epipharyngitis can be also observed in persons working into a noxious dusty atmosphere (cement, lime, glass, toxic gases) and in workers from spinning mill or factories with dried atmosphere and higher temperature. It may be also observed in some singers, feeble persons, pretuberculosis, after some infectious diseases (diphtheria, scarlet fever) . Besides the tubal –tympanic catarrh the two diseases can appear as tracheobronchic descendent complications, bronchitis or bronchoalveolitis maintaining that vicious circle of chronic inflammatory pathology of respiratory type. The treatment is similar to that of the diffuse chronic pharingitis with transient improvements.

Pharyngeal Ozena

It commonly accompanies nasal ozena, but sometimes, ozenous process is more stressed in nasopharynx. Histologically, lesions confine to a wide sclerosis affecting all the structural elements of the nasal fossae. Epithelium suffers a metaplasic process with cilli vibratili disappearance, cylindric cells changing to cubic cells, partial keratinization and glandular cells disappearance, chorion, vascular walls and nervous sheaths, all of them enveloped in that process of conjunctive proliferation. Periostium reacts by thickening and the bone undergoing denutrition as a consequence of vessels sclerosis, presents progressive lacunar bony resorption with maximum atrophy at the horn levels, glandular secretion disappearance explaining mucosa dryness and crusts forming. Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 147

Different children‘s contagious diseases predispose to that affection appearance by starting at the beginning of puberty as a preozenous mucopurulent rhinitis ; little developed adenoids removal is not recommended in order to avoid the slow atrophy process; at that stage , general treatment is necessary to make the body fortified; sports would be joined as well. During the ozenous period nasal fosae recalibration surgery refortifies mucosa in the operated area but little influences the atrophic process of cavum, level to which mucosa appeared atrophied, dried covered with purulent secretions or bad – smelled yellow – greenish crusts. The treatment is the same as in the nasal ozena [31].

Pharyngokeratosis

It was described only in 1951, by Baldenweck, when he distinguished it from pharyngeal mycoses to which the former could be resembled due to the palatine tonsil crypts epithelium keratinization , giving birth to certain hard expansions of white- yellowish millet beans sizes or more, with an elvetic aspect, difficult to be detached, leaving a blooding erosion. Besides the palatine tonsils, that aspect could also be met at the level of the lingual tonsil or on the lymphoid follicles of the posterior wall or, even in nasopharynx; the rest of the mucosa was normal or it only presents a slight keratinization. Those prominences appear rapidly or insidious especially in young women [31]. The affection is accidentally discovered having as symptoms just drying, burning or foreign body sensations at the pharynx level. Ethiopatogenically, it seems to be a slow inflammatory reactive process, just like in other affections of the same order of airdigestive mucosae (leucoplasias, larynx pachidermia, pilous black tongue ) . Histopathologically, bony or cartilaginous islands can appear into the endocryptic epithelium and large formation of keratine in the crypts [34]. Pharyngokeratosis is a benign disease; it can suddenly disappear after months since it started, but it could last for 1-2 years without changing its clinical aspect. When amigdalian lesions are a few and not quite characteristic, diagnosis can be made at the tongue basis using indirectoscopy, where those lesions have been permanent and demonstrative. Mycotic formations appear all over the pharyngeal mucosa surface and the microscope reveals leptotrix germ; if that exam is a negative one, hyperkeratosis lesions can be established histopathologically; white anginas are febrile and very painful; tuberculous and syphilitic lesions are ulcerous. Concerning the treatment, some improvements can be obtained after Lugol solution cleaning and other oral disinfected solutions, but the palatine tonsils surgical ablation is still the best approach.

1.5. Adenoids

Normally, at birth, a baby presents a lymphoid tissue layer of 2-3 mm thickness forming Luschka‘s pharyngeal tonsil, on the cavum arch mucosa and posterior wall. That tonsil hypertrophy was called ―adenoid vegetations‖ by Mayer (1870). 148 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

Ethiopathogeny – If sometimes adenoids hypertrophy is congenital due to the total exaggerated exudative lymphatic diathesis in some children, for several times the adenoids chronic inflammatory pathology have been obtained; the age of expressing symptomatology and complication appearance is between 3 and 6 years. Usually adenoids regresses toward puberty but they can be continuous up to the adult age, maximum frequence of chronic adenoiditis being in school aged children. Main cause for that hypertrophy to appear is recurrent infection [19] sucking baby‘s and children‘s acute rhinitis; the later is due to both the microclimate variations, cold and wet climate and childhood infectious diseases. Another factor could be congenital lymphatism characterized by all lymphoid formations and lymphatic ganglia hyperplasia; lymphatic children are pale, with cervical micropolyadenopathy and frequent skin and mucosa affections. Pathologic anatomy. Lymphoid tissue layer present at birth becomes pathologic if it is more than 5 mm. The package of adenoid vegetations usually appears as an unique tumoral, formation globulous, with parallel or fan-shaped channels, soft, grey-pink formation (Figure 12, 13). Macroscopically it is a hypertrophy but not a neoformation or a degenerescence; its structure is similar to the ganglionary rich vascularized lymphoid tissue [32].

Considering their volumes, adeniods can be:  Large, occupying the whole cavum thus leading to problems of nasal obstruction;  Middle, partialy obstructing the choans;  Small, only on the arch or spread throughout the cavum, especially acting by their septicity and giving many complications at the distance (Figure 12, 13).

Microscopically, two forms of adenoids hypertrophy were established:

(a) Hyperplastic form characterized by germinative centre numbers increase, should be considered as a functional hypertrophy in the context of the immunologic activity of the body frequently exposed to different acute respiratory infections (Figure 1); (b) Hypertrophic form, developed as a consequence of the anterior inflammations; it is characterized by the excessive development of the connective tissue interspersed through the lymphatic follicles [32] (Figure 2).

Clinically and functionally, the most important symptom is the nasal respiratory failure. Adenoidian children use their mouth to take breath especially during the night, having an interrupted and noisy sleep, sometimes with stridulous laryngitis crises and suffocation because of the tongue basis lowering. Abundant mucopurulent secretions are permanent and the voice becomes a nasal one (closed rhinolalia). Because of the tube infection and obstruction preventing the normal airing of the ear drum thus favouring both the chronic serous otitis and transmission hipoacusia appearances [5]. The following reflex disturbances appear: frontal cephalea, Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 149 cough provoked by the secretions flowing towards the larynx posterior commissura, night enuresis, various habits. Some authors consent that certain endocrine disturbances especially hipophysal ones would occur. Adenoidian children are apathetic, absent- minded, psychically retarded [8]; sometimes parents make a mistake by ignoring all that signs. As objective signs of probability, adenoidian facies is characterized by: pale face, opened mouth, narrow nose, badly implanted teeth and discovered by the upper lip retraction, face lack of expression, tired lock, dysmorphias are also interested in the thoracal cage with the vertebral column [31]. By palpation we may established subangulomandibulary and/or occipital polyadenophaties. In buccopharyngeal exam, palatine tonsils, mostly hypertrophied, lingual tonsil, and ogival-shaped palatine arch can be also established. Pharynx posterior wall presents lymphoid granulations covered by mucopurulent secretions flowing from cavum. In anterior rhynoscopia, a lobulated mass with bright reflexes, limited lowery, mobile in phonation namely adenoids can be seen in cavum sometimes. In posterior rhynoscopy or endoscopically, those vegetations can be observed; they may cover the vomer posterior border and the choanas according to their hypertrophy degree. If those manoeuvers can‘t be performed we practice rhynopharingeal touch, gently, at cold, by means of which the volume, place and consistence of vegetations can be appreciated. In the case of a softer consistence a slight bleeding occurs due to the tumor rich vascularization. Otoscopy visualizes rosette – shaped ear drums, retracted due to tube permeability disorders. Clinic forms. Acording to age, two adenoid vegetations can de dinstinguished:

- suckling baby‘s adenoids, quite frequent, prevent sucking by choans obstruction and necessitiy of an oral breath, having atrepsia as a consequence. Acute adenoiditis, by its mucopurulent secretions, gives respiratory infections and digestive compications, latent or supurative otitis and more rarely, retropharyngeal abccesses. The diagnosis is made by Lubet-Barbon pincers that is used to remove those adenoids in suckling babies. Then, rachitism and thymus hypertrophy should be searched, constituting Palthauf‘s thymolymphatic state. Investigations and surgery should be carefully performed in order to prevent a sudden death which is frequent in sucking babies; - adult‘s adenoids – even they normally disappear up to the age of 15, sometimes, adenoidian residuals can be met in a adult, on the palatine arch in the proximity of the tube, thus favouring chronic adhesive otitis and gradual deafness and chronic catarrhal rhynopharyngitis. A special clinical form of the latter is chronic abscess placed in Thornwald‘s bursa , with abundant mucous or mucopurulent secretions, with cephalea and pharyngeal aches.

Complications. A direct ratio between the adenoid volumes and complications severeness produced by the latter was not established. Sometimes, reduced volume adenoids with small hidden abscesses into the lymphoid tissue give increased disorders. The most frequent complication is the acute adenoiditis expressing fever and the presence of some mucopurulent secretions in the pharynx. Also, childhood otitis media can be due to those 150 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu adenoids as it was possible that a simple tube catarrh occurred with gradually deafning or an adhezive otitis with ear drum retraction and ossicles anchylosis. Other times, catarrhal or discrete, repeated supurative otitis can appear with simple otalgia and their various complications or a chronic tube otorrhea [5, 8]. Adenoids can also determine mucopurulent chronic rhinitis, sinusitis, lacrimal and occular pathways infections( blepharitis, conjunctivitis, eczemas), descendent respiratory infections syndrome (recurrent bronchitis with trachea-bronchic adenopathies) disphonias by interarytenoidian laryngitis by secretions flowing from rhynopharynx. Suckling babies‘stridulous laryngitisis also determined by those adenoids. Rhynopharyngeal infection hotbed, as a distant complication, can determine entherytis , chronic appendicitis, nephritis persistent albuminurias, recurrent rheumastism [31]. Positive diagnosis is confirmed by the anterior rhynoscopy and especially posterior rhynoscopy or by cavum touching which reveals adenoids, to which various symptoms are added to strengthen the diagnosis of obstructive adenoids. Differential diagnosis is made to all the nasal and nasopharyngeal diseases having as a dominant symptom the nasal obstruction: nasal septum deviation, hypertrophic rhinitis, allergic rhinitis, nasopharyngeal polypus, choanal imperforation, nasal wings athresia , nasopharyngeal fibroma, atlas anterior arch thickening, cavum chyst or cancer, infantile preozenous chronic rhinitis; then , chronic rhinitis with abundant mucosities on the fossae floor, due to some nasal mucosa debility that may persist after the adenoids ablation, too, and can be improved by vitamin A and thermal cure [31].

Prognostic depends on how early adenoids have been removed, considering the multitude of disorders and complications they could determine [29].

Treatment is a surgical one (adenoidectomy) which may be performed whatever the patient‘s age. In babies, operation is made only if the adenoids determine respiratory disorders, with a noisy sleep, deglutition disorders, suckling impossibility, with repeated acute adenoiditis joined by complication or by a neurotoxic syndrome of any other reason than food [19]. In a child of 5, surgery is best performed; at that age adenoids give the most numerous complications; earlier, even a successful surgery requires a lymphoid tissue repairing due to the compensatory hypertrophy of the lymphoid follicles spread throughout the pharyngeal submucosa. Also, any patient undergoing an otic or othomastoidian surgery should not be considered cured provided that adenoidectomy was performed, as any rhynopharyngeal infection hotbed increases and keeps an otic complication . Surgical approach is improved by antilymphatic treatment, immunoglobulotherapy (gammaglobulins), vitaminotherapy (A, D, C) climatotherapy (dry semialtitude climate, heliomarine cure) and thermal cures ( arsenic and sulphurous waters). To combat the habit of oral unphysiologic respiration, nasal respiratory reeducation is recommended and to correct the dental implant decisions, orthodontomaxillary treatments are perfomed as well [31].

Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 151

1.6. Adult’s Lymphoid Residuals Pathology

Pharyngeal tonsil Luschka involution process and that of the peritubal lymphoid groups which occur towards the age of 15 doesn‘t end always with the complete disappearance of those formation. Sometimes, in a cavum careful exam of some adults (age between 20-40) complaining of pharyngeal diseases, we could establish residuals from the pharyngeal tonsil or lymphoid conglomerates in Rosenmuller‘s fosetts. Acute, especially chronic diseases of those residuals express by symptoms at distance whose recovering is not possible if the starting pain in cavum hasn‘t been searched. In anterior rhinoscopy, after the horns weakening, or by nasal endoscopy, smooth lymphoid residuals covered or not by translucide or mucous secretions flowing on the posterior wall of the rhinopharynx can be observed on the epipharynx posterior and superior wall . In some cases, those lymphoid residuals in adult can constitute the site of some abscesses (Thornwaldt‘s abscess of Luschka‘s pharyngeal bursa ), or retention chysts at that level. In posterior rhinoscopy, lymphoid buds in Rosenmuller‘s fossets or the pharyngeal tube can be observed. Besides those lymphoid formations, postinflammatory or postadenoidectomy scars can be noticed. Those cicatricial staps are sagittally directed and laterally placed into the Rosenmuller‘s fossets, ranging from the Eustachio‘s tube pharyngeal oriffice the lateral side of the cavum arch thus separating many recesses and having as a consequence the tube pavillion deformation and frequent middle ear inflammations due to the lymphoid follicles superinfection, at that level. Symptomatology. Permanent infection of those lymphoid recesses lead to a chronic catarrhal pharyngitis which first expresses by an early morning coughing when the changing of the body position rallies secretions accumulated during the night into the tracheobronchic tree; spasmodic, persevering cough with mucous, viscous, or mucopurulent expectoration; that cough originating from the need of getting rid of the secretions flowing continuously into the pharynx. Secretions flagging at the posterior commissura level of larynx, then the pharyngeal burning sensation and cephalea settled at fixed point, under the external occipital protuberance; strong, pulsatile cephaleea which is exaggerated when the head moves, with a slight ache of the nafe muscles without ceasing when medical treated, all of them can be added to that cardinal symptom. Cephalea is determined by the abscess or the retention cyst from the medial recess (so called Tornwaldt medial syndrome) and from the lateral scaring recesses, which is different from the sphenoidal sinusitis cephaleea which is diffuse. During some acute rhynopharyngitis, those recesses are kept into the infections process, inflamed lymphoid tissue closes diverticuli thus producing retention with subangulomandibular ganglia capture, with cavum slight medial red swelling or central yellow area due to the formation oh the abscesss which should be incised. Sometimes, that Tornwaldt chronic abscess opens suddenly, mucopurulent secretions flowing down the pharynx posterior wall besides giving the patient a subjective cacosmia. Tornwaldt chronic abscess just like the retention abscesses from the cicatricial diverticuli has to be considered as an infections hotbed with permanent mucopurulent flowing, cephalea with orbito-temporal irradiations, giving the patient a state of asthenia with prolonged sub febrility and hyperleukocytosis [31]. 152 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

Treatment is a surgical one : classic adenoidectomy or by thermic ablation with suction cautter in the case of epipharyngeal lymphoid residuals; incision and abscesses drainage or retention cysts from that level, under endoscopic control [19, 31, 38].

1.7. Chronic Tonsillitis

Palatine tonsil belongs to the Waldeyer lymphatic ring, lymphoid structure placed at the main ―gate‖ of antigens penetration into the body, playing an extremely important role concerning the body antiinfections defence. Palatine tonsils placed at the airdigetive pathways crossing are exposed to an uninterrupted contact both to all the buccodental saprophyte germs and the viruses and pathogene or saprophyte bacterias in the air or food. Those can explain the acute sickness frequence of those organs, acute anginas and periamygdalian abscesses, in all ages, though the hundred of thounsands of lymphocytes from tonsils, immunologic cells, play a primordial defence part against those pathogenic agents (Figure 15). Moreover, the tonsils mostly constituting a permanent chronic disease due to fungic or microbian recurrent aggression, sometimes having as a consequence the granulomatous type changing of the amigdalian tissue [3] present a significant play in some affection at distance ethiologies consequently imposing amygdalectomy. Palatine tonsils can be the site of some acute or chronic inflammations (tonsillitis or amygdalitis ) [8]. Under those circumstances they become hypertrophied, red or they may be covered by a white- grey false membrane. Despite the widely antibiotherapy using [22, 25] tonsils are frequently recurrent and rebel to the antibiotherapic treatment (National Centre for Health Statistics). The evolution to chronic stage by amygdalian repeated acute accesses is due to both their anatomic topography and structure favouring the formation of really permanent bacterian biofilms on the amygdalian surfaces, which leads to an incresead sensitivity towards the microbian aggression but also a special resistence to local or systemic applied antibiotherapy. Due to that discrete evolution, chronic tonsillitis can not be certified such as, because the symptoms are totally poor. That‘s why sometimes the specialist physician hardly can state that, in a certain case, tonsils constitute an infectious hotbed wich, therefore, should involve the ablation of the former and anatomopathologic exam single, that is not so cheap, would sometimes reveal real granulomatous type reaction at amygdalian level [3].Chronic amygdalitis can be divided into 3 completely distinquished groups [31] such as:

- cazeous chronic amygdalitis – most frequent but also most harmless and slightly diagnosed - infecting chronic amygdalitis which is expressed by recurrent local acute accesses or, by determinations at a distance, thus constituting the so-called ―infectious hotbead‖; - simple hypertrophic amygdalitis which is especially observed in children (Figure 15).

According ti the oropharyngeal obstructive syndrome, 5 stages of amygdalian hypertrophy are described [1, 8, 32]such as: Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 153

- stage 0 – intravelic tonsils; - stage I – slightly hypertrophied tonsils, 25% reduced air flow; - stage II – medial hypertrophied tonsils, 25-50% reduced air flow; - stage III – incresed hypertrophied tonsils, 50-75% reduced air flow; - stage II – huge hypertrophied tonsils, more than 75% reduced air flow (Figure 14);

Chronic amygdalitis represent the most frequent lesions within the pharyngeal inflammatory pathology [19] with multiple locoregional complications ( acute otitis media, catarrhal otitis, adhezive otitis, supurative otitis with hypoacusia, mucopurulent chronic rhynitis, sinusitis, occular and lacrimal ducts diseases, descendent respiratory infections) and complications at a distance ( glomerulonephritis, joint rheumatisma, endocarditis, enteritis, appendicitis, persistent albuminurias, etc.) Also, chronic tonsillitis can constitute the specific diseases site such as: tuberculosis and luetic lesions, but they can also be the site of some maligne lesions [37].

Cazeous Cryptic Chronic Amygdalitis

It is characterized by the presence of some cazeous plugs into the amygdalian crypts, which are eliminated after some time but they become recurrent after that . It is so much a common condition that we hardly consider it a pathologic one. Cazeous plugs show a yellow – saffron like coloured, they are muddy and fetid, about 2 mm diameter, the largest of them are extracted from the tonsil upper pole by pressing the supraamygdalian recess. Those cazeous plugs are made up of the following : desquamated epithelial cells and altered lymphocytes; cholesterol and crystals of fat acids smelling fetidly; many saproptytic aerobic germs, predominantly alpha streptococcus and anaerobic bacterias from the buccodental flora, especially fusospirills [15, 31]. Tonsils attenuated chronic infection leads to the formation of those plugs maintaining infection; as a consequence, a vicious circle occurs. The cazeous plug then behaves as a foreign body determining a retention in the secretions respective crypt, inflammatory residuals, descuamated epithelial cells, altered lymphocytes, cholesterol, fat acids and polymorphous germs (aerobic common saprophyte flora, anaerobic or fusospirillary flora, Koch bacilli) which, sometimes can form small whitish intracryptic retention cysts. Chronic inflammatory process leads, in evolution, to the excessive development of the supporting conjuctive tissue, with lymphatic follicles disappearance and amygdalian scleroatrophy towards the age of 50-60 [31] (Figure 3). Etiology. Cazeous chronic amydalitis is an affection both of the adolescents and adults up to the age of 50 and it is rarely met in children. Cazeous plugs are especially met in large tonsils; in small tonsils, sclerous tissue surrounding and separate the crypts, favouring the formation and retention of the intracryptic cazeum. Symptoms. Cazeous chronic tonsillitis does not determine any disturbance; it is often accidentaly discovered. Halena intermittent fetidity comes out when the plugs stagnate in crypts, the rare painful pharyngeal accesses constituting the only symptom disappeared when the cazeous plugs had 154 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu been eliminated: some recurrent monochordits with the vocal sound alteration would occur due to those formations [31]. Objectively, tonsils of variable sizes can appear as normal with an increased congestion at the level of the anterior pillar. Seldom, cazeous plugs can be observed if they are not expressed from crypts, by means of a tongue pusher, that manoeuvre is done from upwards to downwards and from outside to inside. An enlarged, unpainful ganglion can be touched subangulomandibularly.

Evolution and prognostic. Besides all that had happened in the focal chronic amygdalitis, tonsils expression by compressing the anterior pillar, besides the cazeum plugs, it didn‘t eliminate any other muddy or purulent secretion. For that reason, that anatomoclinical form of chronic amygdalitis does not determine complications at a distance, therefore, the surgery indication is given by the fetidic halena and the slightly painful congestive, too frequent or prolonged accesses. In this only clinical form, amygdalian retention cysts of variable size can be observed by occlusing a crypt at periphery; the cysts were unique without any subjective symptoms; they can last for years and do not change their aspects; they can be opened by a stilet or a lancet electrocauter , thus determining a purulent, gluey fatidic substance. Those cysts relapse in the some place and have the same aspect if surgery is not performed. When such a cazeous mass dehydrated and calcium impregnated an amygdalian calculus is given birth to, which lead to ulcerate mucosa to get out. That amygdalian lithiasis is very rare and it can be removed easily [31].

1.7.2. Chronic amygdalitis an infectious hotbed In that clinical form of the chronic tonsillitis, the first question to ask a patient is wheather he/she presented amygdalian acute recorded acceses since childhood; that‘ s because the diagnosis is first based on patient‘s answer which, subsequently would be correlated to the clinical exam and to the laboratory paraclinic exams.

Etiopathogeny Amigdalian crypts constitue the main chronic infection hotbed because they are covered by the anterior pillar and the two folds triangular and semilunar, they are completely blacked out when intravelic tonsils; in those cases, the crypts contents cannot be achieved because the mucous glands have no opening at the level of the crypts; palatine tonsils have become an infection hotbed not only by the presence of group A beta hemolithic streptococcus but also the intracryptic retention of all the microbian organic and anorganic products at that level. Nasal obstruction and, consequently, oral breath brings many harmful factors in the respired air, influencing on the tonsils. Cold has direct action on the latter and a reflex action by tegments colding leading to the biochemical processes inhibition at the tonsils level, by neuro vascular disorders of the pharyngeal mucosa. Nasal or sinusal infections may influence on the tonsils, just like the eruption accidents of the molars. Adenoids from childhood can cause tonsils chronic infections; for that reason it is recommended that, first of all, adenoidectomy should be perfomed at that age, leading to Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 155 renouncing the tonsils ablation by the disappearance of the obstructive type disorders at that level. Numerous saphrophite aerobic and anaerobic bacterias specias have been revealed into the amygdalian crypts, microbian flora resembles to the bucodental one. The following belong to the anaerobics; Vincent fusospirillary association, Bacteroides fragilis , B. fundiliformis, B. ramosus. B.fundiliformis is responsible for the postangine septicemia. The following streptococci belong to the aerobic seria: H. streptococcus, Haemolitic Streptococcus with more groups among which only A is pathogenous for human being. All those saprophytic agents, normally can become pathogenic under congestive conditions, leading to pultaceous angina [7, 15, 31]. If the patient states that, in his/her records, repeated anginas has occured, with abscesses or periamygdalian flegmons (supurative complications) or without any of them, the diagnosis of chronic focal amygdalitis does not require any other objective signs. When those records do not exist, in the case of some patients with a ―focal infection‖, objective signs should be carefully looked for to diagnose the infectious amygdalian hotbed. When repeated anginas have been absent in patient‘s records we should take into account the pharyngeal painful repeated accesses on the basis of a cazeous cryptic chronic amygdalitis, together with the clinic and laboratory exams (ASLO,VSH over normal, leukocytosis or gamaglobulins increase). Objectivelly, the presence of the lactescent purulent secretions into the amygdalian crypts, which were established when tosils had been compressed, with/without cazeous plugs expulsion, can constitute a reason for the favour of the focal chronic amygdalitis, as on the occasion of a congestive access, repeated acute anginas and periamygdalian abscesses can be determined. Tonsils sclerous atrophya formed after repeated inflammations had as a consequence the crypts narrowing, haltering and deforming and having a microbian polymorphism retention beside the cholesterol, fat acids and numerous cells at that level. Permanent congestioned anterior pillars would constitute a sign of a chronic amygdalian hotbed and repeated infections in that zone. A small subangulomandibular ganglion, unpainful, persistent, if increases its volume, becomes sensitive at a pharyngeal painful access and would worth for diagnosis [31]. Differential diagnosis can be made with:

Pharyngoamygdalian acute inflammation ( reccurent anginas); Amygdalian specific infections (TBC, lues); Benign tumoral or pharyngeal malign pathologies including hematologic diseases; Abnormal elongated stiloid apophysis press on the tonsil leading to disphagia, odinophagia, foreingn body sensation and slings; it may be established by bimanual palpation and radiographic exam; Pharyngeal paresthesias – the patient feels pain out of meals, he/she can describe the painful sensations minutely, and, when he/she has his/her meals, the pain cease; Periamygdalian and slow intraamygdalian phlegmons with subacute evolution, otherwise very rare forms, grow with their usual clinical features; Amygdalian calculus give a stony sensation and it is onesided.

Focal chronic amygdalitis complications:

156 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

- Periamygdalian phlegmons constitute the most frequently met complications. During an acute amygdalian access, the infection from the bottom of crypt spreads to the periamygdalian cell tissue; - Ulcerous cryptic amygdalitis (Moure angina). At the level of a infected crypt, an ulceration covered by fals membranas occurred; bacteriologic exam established the presence of streptococcus associated to fusospirils. General symptoms have been minimal and healing occurs in about 8 days. - Amygdalian chronic infection can keep up a bronchopulmonary inflammatory reccurent pathology appeared within an acute tonsillar access; - Appendicitis is frequently met coexisting with chronic amygdalitis denoting a close anatomophysiologic relationship between tonsil and appendix (the intestinal amygdala); - In case of certain higher virulence streptococci, anginous septicemia may occur; infection spreads on the venous pathway (pharyngeal and peripharyngeal venous plexus). Septicemia with embolias in all the main internal organs occurs more frequently. Those complications became extremely rare due to antibiotics [8, 9, 19, 31].

Pharyngeal infectious hotbeds. The problem of the pharyngeal infection hotbed, generally, and the amygdalian hotbed, especially, was initiated by Billings in 1912 and it is still under debate up today as it is parthy disputed. Therefore, Danielevicz stated that both the amygdalian process and nephritis or rheumatism to which they coincide, are all secondary reactions of a rhynosinusal infection. Billings, the founder of the infection hotbed theory, holds that the tonsils, appearantly the most innocent, even small organ, can contain one or more infection hotbeds. That statement proved completely unwarranted as neither bacteriologic exam nor the histopathologic one of the apparently rigurous normal tonsils and without a pathologic past , which had been removed, did not bring the formal proof and, those affections for which tonsils were considered as guilty and, consequently removed, were not cure or even improved. Though an amygdalian or dental infection hotbed was established we could not surely say that is constituted the etiological factor in some focal infection of the body as it was known that most of the chronic infection hotbeds were well tolerated [31]. Serologic tests were then used. Starting with Vigo Schmidt‘s amygdalian test, followed by tens of other tests and ending with ―0‖ antistreptolysine antibody titer dosage (oxygen labile) from blood (ASLO) the latter being used most frequently nowadays. Chronic amygdalitis complications at a distance from an infection tonsil hotbed:

- ocular: iridocyclitis (uveitis), chorioretinitis ; - respiratory: chronic bronchitis( some asthmatiform cases), apical infectious processes or supurative peribronchitis (septicemic complication ); - cardiovascular: septic endocarditis, myocardic abscesses, pericarditis (septicemia mechanism), carditis from acute joint rheumatism, phlebothrombosis; - digestive: dispepsia by piophagia( in hipoastenic persons); Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 157

- renal:acute and chronic glomerulonephritis, ―in hotbed‖ nephritis, interstial nephritis (septicemia mechanism); - osteoarticulary: acute articulary rheumatism,subacute poststreptococcic rheumatism (treatable), postanginous oligoarthritis, osteomyelitis and supurative arthritis (septicemia mechanism), rheumathoid polyarthritis increase, anchylosing spondilitis and collagenosis (lupus erythematous systemic, sclerodermia, polymyosia, autoimmune vasculitis); - dermic: tegmentar vasculitic manifestations in vascular diseases (rheumatoid purpura), polymorphous erythema, chronic eczema; - neurologic: choreiform manifestations within the acute articular rheumatism , nonspecific psychic disorders ( astheniform type, generally) peripheral nevritis, Sluder syndrome, salivary or lacrimal hypersecretion, ophthalmic migraine; - septicemia with hotbed germs (very rare in antibiotherapy epoch) [31].

Despite the efforts made to establish a drug therapeutic protocol of the amygdalian chronic infections both in a child and an adult and we really refer to a group A beta haemolitic streptococcus disease [18, 22, 23, 24, 27] to prevent the appearance of the complications at a distance – the treatment is the surgical one amygdalectomy or amygdalotomy, according to clinicotherapeutic necessities [35].

1.7.3. Scleroatrophic chronic amygdalitis Scleroatrophic chronic amygdalitis is a result of tonsils sclerous tissue invasion and represents the most dangerous form of chronic amygdalitis, with toxiinfections dissemination at a distance ( rheumatism , glomerulonephritis). When clinically examined, tonsils were small, hidden among pillars, hardly visible sometimes [31].There is an adage trying to explain the correlation between the amygdala macroscopic aspect and its infections nature : ―more guilty more hidden ― and the treatment is undoubtly a surgical one [2]. Microscopically the following were remarked: surface epithelium erosions especially at the crypts level, unequal hyperplasia of the lymphatic tissue; capsular and pericapsular cell tissue lesions with scleroses not regulated thickening of the interlobular septae and subepithelial abundant collagenous fibrosis (Figure 2, 3). Most oftenly induced by the repeated inflammatory accesses and different microbial associations between aerobe and anaerobe germs, but especially by the A group haemolytic beta streptococcus, scleroatrophic focal amigdalitis by pathogenous agents retention and by accumulation of local cell degrading products, by crypts orifices blockages constitute a chronic infectious hotbed responsible for the most of the local and distant complications [7]. Immunohistochemical reactions using CD20 antibodies revealed that the clear center of the lymphoid follicles was preponderantly occupied by the B lymphocytes (Figure 9). The B lymphocytes increased density showed the intensification of the cell differentiation and proliferation processes taking part into the tonsil lymphoid follicles as a consequence of the antigens presence at the Waldeyer lymphatic circle level. A minute analyse of the microscopic images revealed the presence of some gaps of reaction as a proof that other cells also existed into the germinative clear center which did not give positive reaction to CD20, there for they did not belong to the B lymphocytes- lymphoblasts categories. Unlike the B 158 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu lymphocytes, the T lymphocytes, specially revealed by the immunohistochemical reaction to the CD45 and CD 3 antibodies, appeared preponderantly disposed at the lymphoid follicles periphery, into the follicular cortical but also into the inter and perifollicular lymphocitary infiltrate (Figure 6, 7, 8) [6, 12].

Figure 6. T lymphocytes‘ distribution in the tonsils. They are increased in the inflammatory process around the follicles, Immunoassay using CD3, x 1000.

Figure 7. T cells are rarely encountered in the lymphoid follicles. Immunoassay using CD3, x 2000.

Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 159

Figure 8. T cells highly represented in the inflammation process around the follicle. Immunoassay using CD3, x 2000.

Figure 9. B lymphocytes‘distribution. They are highly represented in the clear center of the follicle and very rare in the follicular crown or around the follicle. Immunoassay using CD20x 2000

Immunostainig with CD68 revealed the presence of macrophages. In the cases studied by us we could established the existence of an increased number of CD68 positive cells of great sizes, which were present relatively homogenous at the germinative clear center level (Figure 10).The existence of macrophages at that level pointed that following the lymphoblastic proliferation intense processes, abnormal B lymphocytes could appear being 160 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu recognised and taken away by macrophages. An intense positive reaction to CD68 was also observed in the superficial tonsil corion; immediately under the basal membrane of the covering epithelium and even in the structure of the epithelium (figure …). The macrophages presence at that level is ordered by the existence of the pathogenic germs from the tonsil surface and even from the superficial corion. CD68 positive cells were more numerous into the amigdalian crypts epithelium, probably due to the micro organisms and cell detritions accumulation and remainings .

Figure 10. Macrophages‘ distribution in tosillar parenchyma. They are predominant and numerous in the clear centre of the follicle. . Immunoassay using CD68 x 2000.

Figure 11. Immunoassay using PCNA x 2000 in order to reveal proliferative processes and germination in the follicular clear centre.

1.7.4. Hypertrophic chronic amygdalitis It is especially met in children, in which, due to their age, lymphatic system is at the height of the activity. Embryologically, palatine tonsils appear towards the end of the fetal life, their complete development takes place at the begining of the second year. Hypertrophic chronic amygdalitis is exceptionally rare in suckling babies; it is especially observed during Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 161 the first childhood and very frequent in the second one; normally, that hypertrophy bears an involution process with aging. In adults, hypertrophic chronic amygdalitis can appear and persist following repeated infections [31].

Etiology: In children, adenoids are joined by the hypertrophy of both the palatine tonsils and Waldeyer‘s lymphoid follicles; due to the exaggerate activity of the lymphatic system constituting the constitutional factor. The frequence of the infectious diseases at that age represents the predisposing infectious factor for the amygdalian reaction and hypertrophy [16].

Pathologic anatomy. Simple (soft) hypertrophy of palatine tonsils is a soft hypertrophy as it‘s about the lymphoid tissue size increase given by the germinative clear centre hypertrophy. Tonsils are pale, soft, friable and depressible, with a very abundant lymphoid tissue; epithelium does not show any inflammatory lesions and capsules and interlobular spaces have a normal structure. Otherwise, in an adult, hypertrophic chronic amygdalitis is a hard hypertrophy with many inflammatory lesions and lymphoid follicles suffocated by the amygdalian conjunctive tissue thickening that follows acute repeated accesses [31, 32, 39] (Figure 1, 2, 14).

Figure 12. Endoscopic image of the adenoids with coanas partial obstruction.

162 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

Figure 13. Cavum lymphoid tissue hypertrophy in chronical tonsillitis

Symptoms. By their sizes (Figure 14), tonsils connecting sometimes to each other on the medial line, can determine many respiratory disturbances; inspiration is difficult due to the buccal – pharyngeal isthmus closing and upside pushing of the palatine veil ; therefore , the child snors while sleeping due to the mechanic respiratory failure; he/she also feels difficulty in swallowing which is also a mechanic problem. Voice is stipling as if the child speaks with his mouth filled (amygdalian voice). Also, pharynx tickling sensation can appear thus determining the child to a reflex dry, amygdalian coughing.

Figure 14. Soft hypertrophic chronic tonsillitis in children. Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 163

Figure 15. Acute tonsillitis an infectious hotbed.

The child complains of tiredness, indisposition and sometimes he/she presents subfebrilities after efforts . Amigdalian hypertrophias -anatomoclinical forms:

Pediculated , tonsils exceeding out of the pillar; Covered sizable tonsils, covered by the anterior pillars or, by the two refolds (triangular or semilunare ); Plunged tonsils, more developed at the lower pole and descended towards the basis of the tongue [16, 31].

Differential diagnosis is made by the simple hypertrophic form of the tuberculosis which is onesided in most of the cases; their mucosa is pale and it is joined by both the cervical and mediastinal adenopathies; those children use to have a loaded heredity and intradermoreaction is positive; if any doubt, biopsy should be made. Hypertrophic form of the secondary lues is a sudden hypertrophy generalized to the entire Waldeyer ring and it is joined by the muco-cutaneous symptoms. Sarcoma starts with only one amygdala hypertrophy leading to disphagia, dyspnea and it joined by a satellite adenophathy . Maligne lymphogranulomatosis (Hodgkin disease) gives an amygdalian hypertrophy concomitantly with a cervical adenopathy and splenomegalia and biopsy should be made. Lymphoid leukemia gives a large, irregular, violetish hypertrophy of the tonsils that opens the buccopharyngeal isthm, generalized adenopathy, leukocytosis (200.000-300.000/mmc; ) with 99 % lymphocytes [31]. In pupils , adenoids are joined by hypertrophic chronic amygdalitis in 14-50 % cases. As it is well-known, under certain antigene –antibody contact conditions (viral or microbian acute infections, increased efficiency to slight infections) adenoids become hypertrophied by compensation along with the palatine tonsils ; with time, that compensation makes the function of those organs be disturbed with the appearance of the respiratory mechanic, deglutition and immunologic disorders. Given the fact that chronic tonsillitis is a childhood 164 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu feature, surgical intervention should be carefully prepared and suggested just to prevent and avoid complications. Surgical treatment consists of total bilateral extracapsulary tonsilectomy; in hypertrophic forms without general lesions and focal infections but with minimum of mechanic obstructive lesions tonsilotomy, cryocoagulation or laser should be performed, to diminish palatine tonsils volumes [20, 21]. In some cases, adenoidectomy is performed between 2-5 years old thus determining the size secondary diminishing of the palatine tonsils. If the amygdala size volume diminishing was not achieved, then in the second stage, amygdalectomy should be performed. Amygdalectomy indications should be carefully given in children, by co-operating with the pediatrist, following a minute exam of the patient, as, there is an increased tendency to exaggerate when practicing such as intervention having some unpleasant consequences for the patient due to the important part which the amygdalas play concerning the body antiinfectious defense [17, 20, 21]. As regarding the frequency, the surgical indications are the following:

Chronic amygdalitis – infection hotbed locoregionally complicated by recurrent anginas and periamygdalian phlegmons; Hypertrophic chronic amygdalitis determining respiratory and mechanic deglutition disorders; Cazeous cryptic chronic amygdalitis giving permanent fetidic halena or complicated by the presence of an amygdalian calculus; Recurrent chronic tonsillitis with disphagia or persistent laterocervical adenopathy; Suspecting amygdalian neoplasia; Chronic pulmonary cord, sleep apnea syndrome, talking difficulties, lymphoproliferative pathology [8].

In all those hotbed infections surgical indication should be recommended by co-operation with specialist doctors.

1.8. Lingual Tonsil Hypertrophy

If the lingual amygdala occupies all the basis of the tongue in a child , after the age of 14 it becomes atrophied into the medial part and divides into two simetric halves separated by a smooth channel extending from the foramen cecum to the medial glossoepiglotic refold. Atrophy goes on up to the adult life when there remain only a few follicles on the anterior edge of the gloosoepiglotic fossetts . Just like the other Waldeyer‘s ring amygdalas , the lingual tonsils can get hypertrophied and occupy the two glossoepiglotic fossettes as follows:

Hypertrophy of the lymphoid tissue in the basis of the tongue on the projection area oh the lingual amygdala can appear after an early palatine tonsilectomy or due to the palatine amygdalas recurrent infections which is transmitted to the entire Waldeyer lymphatic circle level, as a rule [31].

Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 165

Symtoms are discrete: permanent foreign body sensation or only in deglutition, pressure sensation, deglutition trouble, reflex dry non-responsive to any treatment cough, slight cervical pain (on the projection area of the large hyoidic horn), pharyngeal node sensation, aerophagy following repeated deglutitions to get rid of the foreign body sensation (bread, bone, hair, etc), up to pharyngeal tenesmus by glossopharynx excitation. The contact of the lingual amygdala to the epiglottis during deglutition and phonation lead to the reflex cough; nervous exciting is taken by the upper larynx nerv ( vagus branch), transmitted to the bulbar centre and then, by means of the centrifugal pathways , to the expiratory muscle. Those peripheral excitations can be also taken by the glossopharyngeal or trigemen leading to the supraglottic cough and permanent irritation. Conclusion is that in a patient with an expiratory chronic or supraglottic cough (without a nasal or pharyngeal cause) we should first think to the lingual tonsil hypertrophy [31]. The treatment consists of reducing the lingual tonsil size by diathermo- coagulation, nowadays by electrocoagulation or surgical ablation [8].

1.9. Tubal tonsils Hypertrophy (Gerlach)

Waldeyer‘s lymphatic ring sometimes presents lymphoid follicles conglomerates at the salpingo-pharyngeal posterior grooves of the tubal orifices, constituting the Gerlach tubal amygdalas. In children , since the Luschka amygdala hypertrophy occurs, Gerlach tonsil compensatory hypertrophy also takes place; the latter increases when rhinopharygeal acute inflammation has repeated and it will usually decrease towards teenage [17, 31]. Those lymphoid follicles covering the tube orifice and leading to transmission hipoacusia, favouring the supurative otitis media during acute rhinoadenoids and holding tympanic mucous otorrhea with the appearance of the chronic serous otitis [38] can be seen when posterior rhinoscopy or a nasal endoscopy is performed (Figure 13). The treatment consists of surgical removal of those tonsils which is performed during adenoidectomy by using a small curet applied on the lateral walls of cavum, very carefully and gently as a sudden surgical manouver at that level can lead to retractile scars and stenosis of the Eustachio‘s tube pharyngeal orifice having as consequences many subsequent complications [33, 35].

References

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[3] Al-Subeih, K. & Katchy, K. (2007). Adenotonsillar granuloma: histopathological correlation - Med Princ Pract., 16(6), 450. [4] Andratschke, M. & Hagedorn, H. (2005). Chronic tonsillitis-pathogenesis, symptomatology and therapy- MMW Fortschr Med., 2005 Sep 29, 147(39), 33-4, 36. [5] Anil Lalwani (2007). Current Diagnosis and Treatment in Otolaryngology, 2 edition, McGraw-Hill Medical. [6] Anne Mansson, Mikael Adner & Lars Olaf Cardell (2006). Toll-like receptors in cellular subsets of human tonsil t cells: altered expression during recurrent tonsillitis Respir Res., Mansson. [7] Bourbeau, P. P. (2003). Role of the microbiology laboratory in diagnosis and management of pharyngitis. J. Clin. Microbiol., 41, 3467-3472. [8] Byron J. Bailey, Jonas T. Johnson, Shawn D. Newlands, Karen H. Calhoun & Ronald W. Deskin (2006). Head and Neck Surgery: Otolaryngology, ed. Lippincott Williams & Wilkins. [9] Page, C., Peltier, J., Medard, C., Celebi, Z., Schmit, J. L. & Strunski, V. (2007). Peritonsillar abscesses (Quincy) -Annales d'Otolaryngologie et de Chirurgie Cervico- Faciale, Vol 124, No. 1, Mars © 2007, Elsevier Masson SAS. [10] Carmen Aurelia Mogoanta, Elena Ionita, Pirici, D., Mihaela Mitroi & Anghelina, Fl. (2008). Chronic tonsillitis: histological and immunohistochemical aspects Romanian, Journal of Morphology and Embryology, Volume 49, Number 3, 275-430. Romanian Academy Publishing House ISSN 1220-0522. [11] Casey, J. R. (2007). Selecting the Optimal Antibiotic in the Treatment of Group A (beta)-Hemolytic Streptococci Pharyngitis. Clin Pediatr, 46, 25S-35S. [12] Dadoune, J. P. (2000). Histologie. 2e edition. Medicine-Sciences Flammarion, Paris. [13] Dan Pereţianu & Marcel Saragea (2003). Imunologia în teoria şi practica medicinei – vol. 2, ed.ALL. [14] Dost, P. (2007). Histology after adenoidectomy/tonsillectomy? : No conformity in Germany concerning the histopathological examination of adenoids or tonsils in children up to the age of 10 years- HNO, Feb, 55(2), 100-103. [15] Gaffney, R. J. & Cafferkey, M. T. (1998). Bacteriology of normal and diseased tonsils assessed by fine-needle aspiration: Haemophilus influenzae and the pathogenesis of recurrent acute tonsillitis. Clin Otolaryngol Allied Sci, 23, 181-185. [16] Heike Nave, Gebert, A. & Pabst, R. (2001). Morphology and Immunology of the human palatine tonsil, Anat. Embryology, 204, 367-373. [17] Hultcrantz, E., Linder, A. & Markstrom, A. (2005). Long-term effects of intracapsular partial tonsillectomy (tonsillotomy) compared with full tonsillectomy. Int J Pediatr Otorhinolaryngol, Apr; 69(4), 463. [18] Iwata, K., Blum, C. M., Linder, J. A. & Stafford, R. S. (2001). Antibiotic Treatment of Adults with Sore Throat. JAMA, 286, 2942-2943. [19] James B. Snow, Snow Wackym, Ashley Wackym, P. & John Jacob Ballenger (2008). Ballenger's Otorhinolaryngology Head and Neck Surgery. Edition: 17 Published by PMPH-USA. [20] Koltai, P. J., Solares, C. A., Koempel, J. A., Hirose, K., Abelson, T. I., Krakovitz, P. R., Chan, J., Xu, M. & Mascha, E. J. (2003). Intracapsular tonsillar reduction (partial Adenotonsillar Disease: Treatment Comes from Histo-Physio-Pathology 167

tonsillectomy): reviving a historical procedure for obstructive sleep disordered breathing in children. Otolaryngol Head Neck Surg., Nov, 129(5), 532-8. [21] Koltai, P. J., Solares, C. A., Mascha, E. J. & Xu, M. (2002). Intracapsular partial tonsillectomy for tonsillar hypertrophy in children, Laryngoscope, Aug, 112(8 Pt 2 Suppl 100), 17-9. [22] Linder, J. A. & Bates, D. W. (2006). Treatment of Adults With Acute Pharyngitis in Primary Care Practice--Reply. Arch Intern Med, 166, 2292-2292. [23] Linder, J. A., Bates, D. W., Lee, G. M. & Finkelstein, J. A. (2005). Antibiotic Treatment of Children With Sore Throat. JAMA, 294, 2315-2322. [24] Linder, J. A., Chan, J. C. & Bates, D. W. (2006). Evaluation and treatment of pharyngitis in primary care practice: the difference between guidelines is largely academic. Arch Intern Med, 166, 1374-1379. [25] Linder, J. A., Stafford, R. S., Shulman, S. T., Tanz, R., Kabat, W., Martin, J. M., Green, M. & Wald, E. R. (2002). Erythromycin-Resistant Group A Streptococci. NEJM, 347, 614-615. [26] Lindroos, R. (2000). Bacteriology of the tonsil core in recurrent tonsillitis and tonsillar hyperplasia-a short review. Acta Otolaryngol Suppl, 543, 206-208. [27] Marcy, S. M. (2007). Treatment Options for Streptococcal Pharyngitis. Clin pediatr, 46, 36s-45s. [28] Mitsuru, G. O. & Takashi Kojima (2004). Expression and function of tight junctions in the crypt epithelium of human palatine tonsils, Journal of Histochemistry and Cytochemistry, Volume 52(12), 1627-1638. [29] National Center for Health Statistics. Ambulatory and inpatient procedures in the United States. Hyattsville, Md: National Center for Health Statistics; 1996. [30] Necat Alatas & Fusun Baba (2008). Proliferating active cells, lymphocyte subsets, and dendritic cells in recurrent tonsillitis -their effect on hypertrophy, Arch Otolaryngol Head Neck Surg., 134(5), 477-483. [31] Obreja, S., Ioniţă, E., Mitroi, M. & Ioniţă, I. (1998). Lexicon al diagnosticului în ORL, Ed. Didactică şi Pedagogică, Bucureşti, Vol I, II. [32] Passali, Damiani, V., Passali, G. C., Passa`Li, F. M., Boccazzi, A. & Luisa Bellussi (2004). Structural and immunological characteristics of chronically inflamed adenotonsillar tissue in childhood, Clinical and diagnostic laboratory immunology, Nov., Vol. 11, No. 6, 1154-1157. [33] Petri S. Mattila (2001). Causes of tonsillar disease and frequency of tonsillectomy operations, Arch Otolaryngol Head Neck Surg., 127, 37-44. [34] Poirier, J., Catala, M., Ribadeau Dumas, J. L., et al. (2000). Histologie. Les tissus. Ed. Masson, Paris. [35] Reichel, O., Mayr, D., Winterhoff, J., De, L. A., Chaux, R., Hagedorn, H. & Berghaus, A. (2007). Tonsillotomy or tonsillectomy?-a prospective study comparing histological and immunological findings in recurrent tonsillitis and tonsillar hyperplasia. Eur Arch Otorhinolaryngol, Mar, 264(3), 277-284. Epub 2006 Sep 21. [36] Richard A. Chole & Brian T. Faddis (2003). Anatomical evidence of microbial biofilms in tonsillar tissues a possible mechanism to explain chronicity, Arch Otolaryngol Head Neck Surg., 129, 634-636. 168 Carmen Aurelia Mogoanta, Elena Ionita and Mogoanta Laurentiu

[37] Kučera, T., Pacova, H., Vesely, D., Astl, J. & Martinek, J. (2004). Apoptosis and cell proliferation in chronic tonsillitis and oropharyngeal carcinoma: role of nitric oxide and cytokines, Biomed Papers 148(2), 225-227. [38] Zenner, H. P. (2002). Terapia practică a afecţiunilor otorinolaringologice, Ed. PIM, Iaşi, (traducere Costinescu V.). [39] Zhang, P. C., Pang, Y. T., Loh, K. S. & Wang, D. Y. (2003). Comparison of histology between recurrent tonsillitis and tonsillar hypertrophy. Clin Otolaryngol Allied Sci, 28, 235-239. In: Handbook of Pharyngeal Diseases... ISBN: 978-1-60876-430-3 Editors: A. P. Nazario, J. K. Vermeulen, pp. 169-191 © 2010 Nova Science Publishers, Inc.

Chapter VI

Management of Swallowing Difficulty in Pharyngeal Diseases

Byung-Mo Oh1 and Nam-Jong Paik2 Department of Rehabilitation Medicine, Seoul National University College of Medicine, 1Seoul National University Hospital, Seoul, Republic of Korea. 2Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

Abstract

In order to prevent repetitive subglottic aspiration or suffocation, coordination of the pharyngeal movement is critical in the swallowing process. However, diverse diseases can cause difficulties in the neuromuscular coordination of the pharynx. Thorough attention to patients' history and careful investigation of the pathophysiology are important in treating the swallowing difficulty. Also, it is mandatory to precisely assess the patient's pathological state with the aid of videofluoroscopic swallowing studies, currently accepted as the standard diagnostic test, and to prescribe adequate treatment based on the test results. Although the clinical trial-based evidence is not sufficient, a satisfactory functional outcome can be achieved in many patients through individually tailored rehabilitation strategies. The purpose of this chapter is to introduce the videofluoroscopic swallowing study, as a standard method for the diagnosis of pharyngeal diseases and to describe the basic principles and approaches of the treatment for pharyngeal dysphagia.

Introduction

Although swallowing is quite a primitive function, even simple regular swallowing involves complex neuromuscular activity which is finely controlled in a temporal and spatial manner. Among the swallowing stages, pharyngeal coordination is of paramount importance especially in order to prevent repetitive subglottic aspiration or bolus asphyxia. Unfortunately, the neuromuscular coordination of the pharynx can be disrupted by a variety 170 Byung-Mo Oh and Nam-Jong Paik of diseases. The resultant impairment is called ―dysphagia‖ or ―swallowing difficulty‖. Dysphagic patients may show inefficient conveys of the food in the oral cavity to the gastrointestinal tract or aberrant transit into wrong pathways other than the esophagus, i.e., to the respiratory tract, nasal or oral cavities. Although swallowing difficulty is currently treated as a disease, it would be more appropriate to regard dysphagia as a functional loss, namely disability. The treatment of swallowing difficulty should not be limited to the biomedical viewpoint, but be approached with a rehabilitative perspective as in the case of other disabilities such as walking difficulties. Each disability has many aspects to be considered, each requiring therapeutic attention. International Classification of Functioning, Disability and Health (ICIDH) classification has traditionally been used to clarify the various facets of disabilities. This system categorizes disability into 'impairment', 'disability' and 'handicap'. According to ICIDH, three approaches can be considered; a restorative approach trying to directly alleviate the impairment which is the disease or the pathophysiology causing the difficulty; a compensatory approach trying to compensate the disability, if any; and an approach considering sociopsychological aspects. Similar approaches can be applied to swallowing difficulty. Its treatment approach, therefore, includes exercise, compensatory maneuvering, and psychological support. In cases of swallowing difficulty of the pharynx, its pathophysiology can be exactly assessed through the videofluoroscopic swallowing study (VFSS) and the fiberoptic endoscopic evaluation of swallowing (FEES). The assessment result enables to prescribe a specific treatment approach for the difficulty in question. Unfortunately, the evidence is still insufficient about the treatment outcome due to the paucity of large randomized controlled trials on specific patient populations. This lack of data is due to the fact that swallowing difficulty is caused by diverse diseases and therefore it is difficult to carry out a randomized controlled trial in homogeneous patients. Despite this unfavorable situation, the clinical reasoning based on careful assessment and state-of-the-art knowledge renders satisfactory treatment outcome for many patients. In addition, the clinical experiments currently under way are expected to provide an important foundation for the clinical decisions in the future. This chapter is intended to describe the general principles for the diagnosis and treatment of pharyngeal difficulties in adult patients with various diseases.

Neuroanatomy and Physiology of Normal Swallowing

Swallowing as well as respiration is quite a primitive function in terms of embryology and phylogenetics. Like other primitive functions such as mastication and swallowing, the neuronal cell bodies for the control of swallowing is also located in the medulla oblongata.[1] The medulla oblongata is an advantageous site for fine coordination of swallowing with respiration and protective coughs. Although clinical management of dysphagia often covers central drives, olfactory and visual perception, and a motor function of the upper extremities,[2] this chapter will focus on the problems around the main pharyngeal process of swallowing. Management of Swallowing Difficulty in Pharyngeal Diseases 171

Traditionally, the swallowing process has been divided into oral, pharyngeal, and esophageal phases. The oral phase can be subdevided further into oral preparatory and oral propulsive stages. A thorough review on the neuroanatomy and physiology of swallowing is beyond the scope of this chapter. Readers can refer to recent published reviews on these subjects.[3, 4]

1. The Cortical control of swallowing

Noninvasive investigation on various brain functions has already been widely used, yet only recently introduced to the field of swallowing neurophysiology. Using transcranial magnetic stimulation, Hamdy et al demonstrated that the cortical control over swallow- related musculature has a bilateral, but asymmetric organization.[5] The study reported that the lateralization of hemispheric dominance to the left hemisphere was not as evident as the human language function. [6] Research with functional magnetic resonance imaging and positron emission tomography showed that multiple brain areas are activated by deglutition, which indicates the complex neural underpinnings made up of sensorimotor and coordination domains as well as an emotional component.[7] Investigation with magnetoencephlogram (MEG) has shed new light on the hemispheric dominance of swallowing control. Volitional swallowing activated the bilateral primary sensorimotor cortex with strong lateralization to the left, whereas, reflexive swallow elicited by a transnasal application of water showed a lesser degree of asymmetry.[8] Another detailed study on the chronological change of neural activity demonstrated a shift of neural activation from the left to right sensorimotor cortex.[9] Similar to the neural activation of language, volitional initiation of swallowing involves the left hemisphere more than the right especially in its early stage.

2. Stages of swallowing and the neural control

The oral preparatory phase refers to the introductory period of food manipulation before the subsequent phases of swallow.[10] Solid food of a volume larger than a spoonful invariably requires this phase. Processing solid food involves unique aspects of food preparation called stage I and II transport.[11] During this oral preparatory phase, food is masticated and mixed with the saliva. A motor component of the oral preparatory phase comprises the trigeminal (CN V), facial (CN VII), and hypoglossal nerve (CN XII). Sensory information is conveyed via CN V and VII.[12] The oral propulsive phase of swallowing is thought to be the start of the stereotyped swallowing reflex, during which the food bolus is conveyed to the pharynx. Since the start of propulsive movement is under volitional control, the start of an oral propulsive stage at least partially necessitates descending cortical input. CN IX, X, and XII play key roles in this phase.[3] 172 Byung-Mo Oh and Nam-Jong Paik

Pharyngeal phase is a process for food bolus to move toward the esophagus by the force of the swallowing reflex in a span of as short as 0.5 seconds. Important issues in this phase are efficiency and safety; Efficiency in the sense of conveying food to the esophagus without leaving much residue behind, and safety in preventing subglottic aspiration. The pharyngeal phase is called the "swallowing reflex" because it shows a comparatively stereotyped pattern and cannot be volitionally stopped once started. Also animal experiments revealed that an electrical stimulus to the internal branch of the superior laryngeal nerve can induce continuous activity of the pharyngeal swallow. Above findings and other knowledge obtained in animal experiments indicate that the pharyngeal phase is mediated by the central pattern generator located in the medulla oblongata. [3, 4] The sensory input applied to the intact oropharyngeal mucosa, however, can induce a gag reflex as well as a swallowing reflex. The determinants of the sensory information causing each distinctive reaction have not been fully characterized even in the animal experiments.[4] In normal swallowing, there is no difficulty for the food bolus prepared in the oral phase and on the way to the hypopharynx to generate the sensory information which induces swallowing reflex exclusively. There are a few mechanisms to prevent the subglottic aspiration in the pharyngeal phase, which are successful in ordinary conditions. These mechanisms include anterosuperior excursion of the hyolaryngeal complex, the epiglottic folding, the adduction of vocal folds, and transient apnea during swallowing. On the arrival of the food to the hypopharynx, the upper esophageal sphincter (UES) opens and the food proceeds down the esophagus. Opening of the UES is facilitated by the anterior hyolaryngeal excursion and intrapharyngeal pressure generated by constrictors. These patterned activities are mediated by the neural control of the swallowing center located in the medulla oblongata mainly via CN IX, X, and XII.[12] The esophageal phase is basically under non-volitional control and the food bolus is conveyed to the stomach through peristaltic movements.

Diseases Causing Swallowing Difficulty in Pharyngeal Phase

Causes producing swallowing difficulty in pharyngeal phase include acute infectious diseases, neuromuscular diseases, structural problems, and iatrogenic causes (Table 1). Etiologies of dysphagia can be classified into two groups; 1) pharyngeal manifestation of the systemic diseases and 2) localized pharyngeal problems such as tumors. Viewed from the natural history of the disease, there are diseases such as acute pharyngitis which produces a transient dysfunction but is completely cured leaving no sequela. On the other hand, there are also cases resulting in permanent dysfunction through surgery or trauma. Another classification on the causes of swallowing difficulties is an approach to classify them as neurogenic or mechanical. The characteristics of these two types of swallowing difficulties are described below in order to help understand the treatment approaches discussed later. Management of Swallowing Difficulty in Pharyngeal Diseases 173

Table 1. Causes of Dysphagia in Pharyngeal Phase.

Pharyngeal manifestation of systemic diseases connective tissue disease – SLE, RA, Sjoegren's syndrome, Systemic sclerosis myopathy and neuromuscular junction disorders – dermatomyositis, polymyositis, myasthenia gravis peripheral neuropathy – critical-illness neuropathy, Guillain-Barré syndrome diseases of the central nervous system – stroke, traumatic brain injury, high cervical spinal cord injury, Localized pharyngeal problem diseases of the central nervous system – stroke, traumatic brain injury, brain tumor, encephalitis cranial nerve injuries infectious disease – viral laryngitis, bacterial laryngitis, fungal infection, laryngeal tuberculosis noninfectious laryngeal disease – laryngopharyngeal reflux disease, angioedema, radiation laryngitis benign conditions congenital – tracheoesophageal fistula, laryngomalacia, cleft larynx vocal cord paralysis Zenker's diverticulum benign tumor – laryngeal cyst, papilloma, hemangioma, chondroma, neurogenic tumor malignant tumor - the nasopharynx, the oral cavity and oropharynx, the hypopharynx and larynx direct trauma to the pharynx tissue loss due to surgery or radiation compression from behind by large osteophytes

1. Neurologic Causes of Swallowing Disorder

Neurologic causes of swallowing disorders can be largely categorized into the damages in the upper or lower motor neuron. Cortical and subcortical stroke, brain stem stroke at or above the level of the pons and multiple sclerosis with brain involvement are examples of the former cause. Diseases of the latter category such as lesions involving the medulla oblongata and lower cranial neuropathies share similar pathophysiologies.[13]

2. Mechanical Causes of Swallowing Disorder

Swallowing disorders derived from mechanical causes can be temporarily generated by acute inflammations or permanent when surgical intervention is used for treatment. Acute inflammatory conditions include Herpes Simplex stomatitis, tonsillitis, epiglottitis, pharyngitis, and retropharyngeal space infection.[14] Many of these cases are transient and improve with appropriate treatment. Carcinomas in the oral cavity, pharynx and larynx, however, can cause permanent disability as a result of surgical resection with or without reconstruction. 174 Byung-Mo Oh and Nam-Jong Paik

3. Recovery of Swallowing Function

In most cases, swallowing disorders occurring after various diseases spontaneously resolves with time. The first step of planning to treat the patient may be to understand the mechanism of recovery. When a systemic disease manifests as pharyngeal symptoms, treating the underlying disease may cure the swallowing dysfunction. In many cases of swallowing dysfunction caused by anatomical deficits after tumor removal operations, there is little chance of functional recovery.

Diagnosis of Swallowing Disorders

1. Clinical Assessment

A. History and symptoms implicating oropharyngeal dysphagia The findings indicative of abnormalities in the oral phase include drooling, impaired mastication and chewing, or holding food in the oral cavity. The symptoms implying problems in the pharyngeal phase are of primary concern in history taking. A fit of coughing while eating strongly suggests subglottic aspiration, which prompts to further investigation. However there might be a silent aspiration so the absence of coughing does not rule out aspiration. Also, pharyngeal residue can stimulate the airway and result in coughing so the clinician should contemplate all the symptoms and signs to make a decision. Other signs that suggest problems in the pharyngeal phase are choking or a wet voice accompanied by food ingestion. The feeding method, current amount of oral intake and self-compensatory strategy should be included in the history taking. The clinician should check whether there was weight loss to rule out the possibility of malnutrition. The volume and frequency of urination should also be checked to estimate dehydration. History or signs of pneumonia are very useful information in assessing the swallowing function.

B. Physical examination The cranial nerves involved in swallowing should be examined to verify the neuromuscular integrity. The trigeminal, glossopharyngeal, vagal, and hypoglossal nerves can be assessed by standard techniques of neurologic examination. Palpating the hyoid and thyroid cartilages while volitionally swallowing is also helpful.

C. Bedside screening tests The usefulness of a screening test is determined by a good negative predictive value, in other words, high sensitivity. Many screening tests have been proposed but only a few are verified for feasibility, sensitivity and specificity for a certain disease. The most common screening method is the water swallow test. It is said to be positive when the patient coughs or shows a wet voice after drinking a certain amount of water. However, researchers differ about the protocols such as the volume of water. Its sensitivity and specificity is known to be 70-80% and 60-70%, respectively. Management of Swallowing Difficulty in Pharyngeal Diseases 175

Other tools such as the blue dye test, cough provocation test, cervical auscultation and pulse oxymetry are also commonly used. The reported sensitivity and specificity of these tests covers wide range; thus, clinicians should be cautious to interprete the results. Recently a screening test for stroke patients has been introduced with high inter-rater reliability, sensitivity and specificity. [15, 16] Also, a screening tool integrating the patient‘s history and physical examination has been introduced. [17]

2. Imaging Studies of Swallowing

A. Videofluoroscopic study of swallowing (VFSS) The VFSS is the most authentic way to check whether there is a swallowing disorder and if so, to assess the severity. It can also reveal the mechanism of the disorder and gives an important clue to treatment planning. The VFSS is widely accepted as a gold standard of the assessment of dysphagia. The patient swallows fluid or food mixed with barium and the tester observes the movements of the related muscles and other soft tissues using a fluoroscope. The protocol can be modified according to the regional food culture; thus, it can differ center by center. One can directly observe airway aspiration and ascertain the effect of various compensatory techniques and exercises. In spite of the advantages stated above, the need of expensive fluoroscopic equipment and the exposure to radiation are major shortcomings. Also, because it cannot be performed at bedside, many patients with serious medical conditions cannot be tested by this method.[18]

B. Fiberoptic endoscopic evaluation of swallowing (FEES) The FEES is obtaining more popularity since its introduction in 1988 by Langmore. [19] This test uses an endoscopy which is already widely adopted in diagnostic and interventional gastroenterology. An endoscope enters the nasopharynx transnasally, procedes through the velopharyngeal port to approach just below the soft palate, from where the tester can observe the oropharynx and the hypopharynx directly. It can be performed at bedside since the patient undergoes the test in a reclining position. The patient's ability to handle food bolus and pharyngeal secretion is readily assessable using FEES. Unfortunately, obvious limitations hinder FEES from superseding VFSS, the current gold standard. The FEES does not give any information about bolus handling in the oral cavity; furthermore, the most frustrating aspect of FEES might be its inability to visualize the pharynx and larynx during the swallowing per se. In addition, FEES provides limited information about the quality of movement such as the degree of hyolaryngeal excursion, UES opening, and pharyngeal constriction.[20] However, there are many merits of FEES. It does not require exposure to radiation, enables direct observation of mucus and vocal cords, and can evaluate sensory function. The fact that it is minimally invasive and can be performed at bedside makes it more fascinating. A recent study reported that it can be safely performed on hyper- acute stroke patients, within 24 hours from the onset. [21] 176 Byung-Mo Oh and Nam-Jong Paik

Management Approach to Improve Swallowing Function

1. Direct and Indirect Therapy

The treatment of swallowing disorders can be divided into direct and indirect therapy according to whether or not it involves oral food intake. Direct therapy involves training by presenting and swallowing solid food or liquid. Since there is a risk of aspiration and asphyxia, the training should start with small amounts and much precaution. When there is massive aspiration and direct therapy seems to be harmful, ROM and strengthening exercise of the organs related to swallowing is the main training. This is called indirect therapy. [10] The choice of training method is made by the safety of the direct swallowing. Therefore, evaluation with VFSS is critical in deciding the treatment.

2. General Medical Care

A. Oral hygiene One should not assume that the oral cavities are clean in patients with acute illness because they are in the state of nir per os (NPO). NPO can reduce saliva production and thereby increase the chance of pathogen colonization. Aspiration of colonized pathogens can lead to aspiration pneumonia, which deteriorates a patient‘s function even further. Dental plaque and caries increase the chance for pathogenic bacteria to grow in the oral cavity.[22] Thus, oral hygiene is the very start of swallowing rehabilitation, reflecting the quality of care.

B. Preventing dehydration, electrolyte imbalance, and malnutrition Patients with dysphagia easily get dehydrated because they tend to reduce ingestion of aspiration-prone food such as liquids. Dehydration can lead to a decrease in saliva production, which puts the patient at risk of pathogen colonization in his or her oropharynx. Dehydration also can weaken the function of the immune system, increasing the risk of secondary infection.[23] High clinical suspicion is essential to deter the vicious cycle of dehydration. A keen observation of skin turgor, a dry tongue, urine output and color of urine is needed. Usual recommendation for minimum daily water requirement is 2-3 liters.[24] Malnutrition is also an important cause of the vicious cycle of deconditioning in patients with dysphagia. Sufficient nutrition is of paramount importance to prevent further functional decline. Increased energy expenditure is commonly encountered in acute hospitalized patients. Many factors affecting metabolic state hinder clinicians from accurately estimating daily energy requirements. However, several reliable methods have been introduced to calculate the patient's energy expenditure to a clinically reasonable degree of certainty. [25] Judicious supply of adequate protein, essential fatty acids, carbohydrates, major minerals, and other trace elements are also vital.[26]

Management of Swallowing Difficulty in Pharyngeal Diseases 177

C. Conditioning exercise Swallowing is obviously a body function which is affected by the general medical condition. Exercise to reverse the deleterious effects of long-term inactivity, surgery, or chemoradiation therapy includes a cardiovascular conditioning and strengthening protocol.[27] Conditioning exercises can enable patients to participate in dysphagia rehabilitation programs more actively.

3. Restorative Approach

A. Increased sensory input Sensory stimulation can be considered as compensation because it has an immediate effect on swallowing-related time indices (discussed below). However, the influence of sensory input on ultimate functional recovery will be discussed in this section. Somatosensory stimulation has been widely used to promote the recovery of motor function in the field of neurorehabilitation. Recent investigation has shown that increased somatosensory input can enhance the effects of the functional hand training and induce changes in the representational map of the somatosensory cortex.[28-30] These studies may present more concrete theoretical base for the use of sensory stimulation to influence motor function in clinical practice. For swallowing function after stroke, functional recovery is known to be accompanied by the expansion of the pharyngeal representation in the contralesional hemisphere.[31] Moreover, the degree of sensory-driven change in the cortical representation was strongly correlated with functional recovery in dysphagic stroke patients.[32] In the studies stated above, electrical stimulation was used as sensory input which differs from thermal, tactile, or vibratory stimulation used more commonly in clinical settings. The most representative treatment is thermal and tactile stimulation and was proven to speed up the oropharyngeal movement. [33] The method is as follows: the patient‘s anterior faucial arch is rubbed up and down five times with a spoon or a laryngeal mirror afterwhich the patient is asked to swallow a small amount of liquid or saliva. This method has an immediate effect but the long-term effects remain to be proven by additional studies. [34]

B. Exercises to build up strength of the swallow-related structures Strengthening training is based on the physiologic capability of the muscle to acclimate itself to a particular demand imposed on it.[35] Progressive strengthening of limb muscles can be performed using well-established protocols. [35] The basic principle of these protocols is to set the loading and repetition according to the repetition maximum (RM) and then train until the point of fatigue. On the other hand, this principle does not apply to the axial muscles and more certainly swallowing muscles becuase it is challenging to define RM. It is also hard to get an isolated movement due to the fact that the myofibers run in various directions in a small space. Moreover, there also are concerns that it is unsafe to induce fatigue in the swallowing muscles because they must be used repeatedly throughout the day. 178 Byung-Mo Oh and Nam-Jong Paik

Regardless of issues mentioned above, resistance exercises are often adopted in dysphagia rehabilitation in clinical situations. Clinical trials using a standardized protocol are required to corroborate the clinical benefit of strengthening exercise.

i. Strengthening exercise for the lips and jaw Lip protrusion, lateralization, mouth opening and closing can be utilized. [1] A typical training session composes of 5-10 sets per day with 5 repetitions of each motion for each session. [36] For example, the therapist delivers manual resistance while the patient holds a straw with both lips. The therapist then gradually increases resistance and training duration thereby improving endurance. [37] ii. Shaker‘s exercise Shaker proposed this training method to facilitate the upper esophageal sphincter (UES) opening. By strengthening the suprahyoid muscles which retracts the hyoid bone anteriorly, we can augment the anterosuperior movement of the hyolaryngeal complex, which may foster opening of the UES. However, in practicality this exercise induces contraction of not only the suprahyoid muscles (i.e., the mylohyoid, geniohyoid, and anterior belly of the digastric muscles), but also infrahyoid ones. One session of this exercise consists of an isometric phase, followed by an isotonic burst. The patient performs this exercise in the supine position. The isometric phase consists of three consecutive cycles of 1-minute head raising and 1-minute rest. It is followed by 30 repetitions of head-raising, i.e., an isotonic phase. The recommended protocol of the above exercise is three sessions per day for six weeks. Controlled clinical trials demonstrated that the Shaker's exercise is effective for patients with impaired UES opening. [38, 39] Additional studies are needed to show the effectiveness of this exercise on other patients with different pathophysiologies. iii. Tongue-strengthening exercise Muscle strengthening inevitably requires resisted movement. Resistance can be applied to the tongue by a tongue depressor or a spoon just as weights are used to strengthen the limb muscles.[40] Resisted protrusion, lateralization, and elevation can be readily performed with straightforward instruction, whereas resisted retraction is difficult to achieve. Patients are encouraged to perform strengthening exercises with five to ten repetitions per session and five to ten sessions a day.[40] A pressure- biofeedback instrument such as the Iowa Oral Performance Instrument (IOPI) is also commercially available.[41] iv. Tongue holding or Masako maneuver The aim of the tongue holding maneuver is to enhance the posterior pharyngeal wall movement and thereby to facilitate bolus transport to the hypopharynx. Patients are instructed to swallow with the tongue held by incisors.[1] This maneuver was previously regarded as a compensatory maneuver, but recent studies show that it increases vallecular residue during swallowing and the risk of aspiration. This maneuver, therefore, should be used as a part of exercise, not as a compensatory techinique. v. Strengthening exercise of the larynx and vocal cords Management of Swallowing Difficulty in Pharyngeal Diseases 179

Reduced laryngeal elevation is correlated with limited food intake after cancer treatment.[42] Conversely, improving laryngeal elevation will lead to gain in a cancer survivor‘s quality of life. When unable to protect the airway by correcting posture or maneuvers like supraglottic swallowing, exercises that can augment the mobilization of surrounding structures of the airway entrance should be performed. For example, making high-pitched sounds or falsetto voice, and the Mendelsohn maneuver are exercises which can improve laryngeal elevation. Vocal cord adduction exercises are both ROM and strengthening exercises.

C. Electrical stimulation on the neck muscles Neuromuscular electrical stimulation (NMES) is a therapy using electrical current to gain therapeutic effect on the muscles with the intact peripheral nervous innervations.[43] NMES has been used widely for the decentralized muscles to prevent atrophy and enhance muscle strength. Randomized clinical trials of NMES on the quadriceps muscles postoperatively showed that NMES is effective for quadriceps training.[44] NMES on the neck muscles has recently been introduced as an therapeutic option for patients with pharyngeal dysphagia.[45] Changes in the cortical representational map were observed in patients who received NMES on their anterior neck.[46] In a study on patients with chronic dysphagia, electrical stimulation only with low intensity showed significant functional improvement.[47] These findings suggest that increased sensory input is one of the mechanisms by which NMES affects swallowing function. Considerable controversy, however, continues concerning its therapeutic benefit. A physiologic study on normal volunteers showed that NMES induces significant descent of the hyoid and larynx at rest and reduces elevation of the hyolaryngeal complex during swallowing, which suggests simultaneous application of NMES with swallowing per se on the supra and infrahyoid muscles can be potentially hazardous.[48] Clinical trials on dysphagic patients reported significant improvement in the NMES group,[49] and mixed results of effectiveness in the active control group.[50, 51] Future randomized controlled trials will be required to confirm the efficacy. In addition, it is yet to be determined which patient population will benefit most from this therapy.

4. Compensatory Approach

A. Maneuvers Many maneuvers have been introduced to manipulate and assist a specific phase of swallowing. Choosing a maneuver must be based on the pathophysiology revealed by VFSS. The efficacy of the maneuver should also be tested by VFSS.

i. Supraglottic/Super-Supraglottic swallow In this technique, the patient closes the airway before swallowing and keeps it closed during swallowing. The patient then coughs out the residue to the oral cavity 180 Byung-Mo Oh and Nam-Jong Paik

immediately after the swallowing process ends. In practicality, the patient is told to inspire deeply, hold his/her breath while swallowing and then cough. Holding one‘s breath while swallowing closes the vocal folds during the whole swallowing process thus preventing subglottic aspiration. Coughing immediately after swallowing is to clear pharyngeal residue.[10] The imaging studies can also help confirm the protective effect of the maneuver. Unfortunately, breath holding does not result in vocal fold closure in some patients[52] and additional techniques to secure the closure may be required. The super-supraglottic swallow is another method to secure airway entrance closure by fostering the anterior movement of the aryteoid. The patient is instructed to bear down the breath holding in addition to the supraglottic swallow technique. The increment of airway closure duration, and quickening of cricopharyngeal opening was proven using VFS findings. [53] Other than airway protection, some biomechanical changes did occur: Increase in hyoid elevation, facilitation of tongue- base movement and magnification of cricopharyngeal opening. [54] Benefit from the super-supraglottic swallow has been demonstrated in patients with head and neck cancer receiving radiation therapy.[54] The supraglottic or super- supraglottic swallow may be contraindicated for patients with a history of stroke or coronary artery disease because these maneuvers are likely to increase the risk of cardiac arrhythmia.[55] However there is only weak eveidence for the effect on other disease entities. ii. Effortful swallow The effortful swallow maneuver is designed to enhance the movement of the posterior tongue and thereby improve clearance of vallecular residue.[56] Patients are instructed to swallow while ―squeezing hard‖ with all of their muscles, [10] or to swallow "as if they are swallowing a large object such as a telephone book."[37] In healthy volunteers, the effortful swallow significantly increases the intraoral pressure and maximal hyoid excursion. It also leads to changes in the temporal characteristics of swallow such as increased duration of laryngeal closure and UES opening.[57] The effects of the maneuver in patients with pharyngeal dysfunction were investigated in an open-label study, which showed no remarkable improvement in intrabolus pressure generation.[58] The effortful swallow can produce an additional effect on the esophageal phase increasing peristaltic amplitudes within the distal esophagus.[59] It is generally believed that the effortful swallow can help patients with pharyngeal weakness. iii. Mendelsohn maneuver The Mendelsohn maneuver was initially intended to improve the degree and duration of UES opening. Use of the maneuver increases the duration of the excursion of the larynx and thereby delays UES closure by maintaining anterior traction on the anterior UES.[60] The patient is instructed to hold the swallow for three counts at the time when the voice box reaches the highest point. Management of Swallowing Difficulty in Pharyngeal Diseases 181

The major benefit of the maneuver is that it allows a larger amount of bolus to pass through the UES. Therefore, clearance of pharyngeal residue might also be improved by this maneuver.

B. Postural techniques Various postures to minimize the danger of glottal aspiration have been introduced. One or a combination of more than two postures can be easily taught. However, evidence for their use on a specific condition is still not so strong.

i. Chin-tuck Chin tuck is one of the most frequently prescribed compensatory maneuvers for patients with a high risk of aspiration. It has been reported that chin tuck induces a change in the spatial structure of the pharynx to make it favorable for glottal protection.[61] Specifically, chin tuck provides favorable conditions for stronger constriction by shortening the distance between the tongue base and posterior pharyngeal wall, and by widening the vallecular space; thus, it can prevent from aspiration which might be caused by the premature bolus loss and delayed triggering of the swallowing. Chin-tuck is also thought to be helpful for preventing aspiration by straightening the alignment of the pharynx and esophagus and by decreasing the dimension of upper laryngeal which is the entrance to the glottis. However, the chin- tuck posture does not change the intrabolus pressure in the oropharyngeal stage [62] and the various chin-tuck protocols used by practitioners have introduced much confusion in evaluating the treatment outcome.[63] These problems necessitate a proper understanding of the physiological changes involved with chin position and swallowing function. ii. Chin-Up or Head-Back Chin-up posture is an adequate approach when abnormalities in the oral phase are more conspicuous than those in the pharyngeal phase. This technique can be used for patients who retain pharyngeal phase integrity but cannot efficiently send food bolus to the pharynx. A patient who underwent partial glossectomy is a case in point. Caution should be exercised, as it may increase the risk of aspiration in patients with severe pharyngeal dysphagia. It can be prescribed combined with the supraglottic swallow maneuver in high-risk patients. iii. Head tilt/rotation Tilting/rotation can be used when there is unilateral impairment in the pharynx. Rotating the head toward the lesion-side narrows the ipsilateral pharynx therefore food transits through the intact side. It is believed that this maneuver also widens the UES and lowers its pressure. In contrast, tilting the head toward the intact side induces the food to transit through the intact side by the force of gravity. Both techniques are maneuvers that can be used when there is a unilateral problem in the pharyngeal phase but the indication may differ case by case. Head rotation will not help reduce the oral residue when coexisting oral phase problems leads to abundant oral residue in the affected side. In this case, head tilting may be more helpful. iv. Reclining 182 Byung-Mo Oh and Nam-Jong Paik

When abundant pharyngeal residue induces overflow aspiration frequently, reclining or supine posture can be tried. When leaning backward, the pharynx becomes caudal to the larynx; therefore, the pharyngeal residue does not flow into the larynx. Residue in the pharynx can be effectively cleared by subsequent swallowing in the same position. Furthermore, the reclining/supine technique is readily applicable because it is the main position for many acutely-ill patients in the ward. v. Postural techniques combined with specific maneuvers There is no need to use just one technique or maneuver at a time. The above mentioned postures and compensatory maneuvers can be applied in combination, resulting in a complementary and, sometimes, synergistic effect. Thorough knowledge of the therapeutic effect of each maneuver and posture is essential to prescribe an appropriate combination of therapy tailored to the patient's pathophysiology. For instance, a patient with unilateral pharyngeal weakness can have additional benefit by adding the Mendelsohn maneuver to the head rotation to the weaker side.[36]

C. Prostheses i. A palatal augmentation prosthesis and an obturator Head and neck cancer survivors who underwent surgical resection of the oropharyngeal structures often complain of communicative and swallowing problems. Absence or defect of the palate can cause severe nasal regurgitation and subsequent aspiration of pharyngeal residue. Partial glossectomy can lead to reduced tongue base retraction and a large amount of oropharyngeal residue. An obturator has a large globular portion which can compensate for the loss of tissue. A palatal augmentation or reshaping prosthesis offers a new enlarged hard palate facilitating tongue-to-palate contact. This type of prosthesis is very useful for patients with impaired tongue mobility such as cancer survivors who undergo glossectomy.[64] Therapeutic goals of a palatal augmentation prosthesis and an obturator can be embodied in one prosthesis with mixed design. ii. Palatal lift prosthesis A palatal lift prosthesis is designed to enhance elevation of the soft palate in patients with velopharyngeal dysfunction. It provides a 'lift' for the soft palate by the backward extension of the palatal segment. Since the extended 'lift' can provoke a gag reflex, a prerequisite for this prosthesis is an increased sensory threshold of the gag reflex. Rigorous adjustment is also necessary. This type of prosthesis also improves speech with reduced nasal air leakage and increased intraoral pressure.[65]

D. Dietary modification Although dietary modification is often prescribed as the first line of management, some oppose to the wide use of this modification on grounds of low compliance and worse perceived quality of life.[40] However, modifying food is still one of the most effective treatments to minimize the risk of aspiration when applied based on the accurate evaluation and correct understanding of the patient‘s pathophysiology.

Management of Swallowing Difficulty in Pharyngeal Diseases 183 i. Categorization of food Food culture differs greatly from country to country. Furthermore, research on the safety of particular foods has not yet generated a consensus. Different systems of food categorization has been proposed.[66, 67] Nevertheless, most guidelines create their own system based on the safety of foods. It is generally accepted that a liquid diet with high viscosity is safer than thin liquids. Categorization of solid foods usually incorporates easiness to chew and aspiration risk. Readers can refer to other published review to get thorough information on the food rheology.[68] Although there is no uniformly accepted categorization system, a viscosity-based categorization of fluid has been used.[69] The suggested system of categorization is as follows.

Nectar-like thickened fluids. Liquid in this category runs well on a smooth surface and can be aspirated using a straw. Liquid barium used in a modified barium swallow study shows viscosity in this range. Other examples include fluid-type yogurt and tomato juice. Honey-like thickened fluids. This category covers wide range of viscosity of 100-10,000 cP[69] or 351-1750 cP.[67] Examples are honey, curd type yogurt, thin soup with starch, and cream soup. Pudding-like thickened fluids. Liquid of this level of thickness showed viscosity > 10,000 cP[69] or >1,750 cP[67] measured by a rotary viscometer. Examples are thick rice gruel, mashed potatoes, and cooked ground meat.

Dietitians Association of Australia and the Speech Pathology Association of Australia suggested a standardized system of labels and definitions about texture- modified foods as well as thickened liquid. This consensus between expert groups provides an opportunity to enhance communication among practitioners and a basis for comparable research outcome. Validity in terms of clinical and cultural aspects, however, remains to be elucidated. General principles of diet modification for dysphagic patients are described below. iii. Considerations in prescribing modified food Thickened fluids are commonly prescribed to dysphagic patients with neurogenic causes, which is based on the assumption of that thickened liquid is easier to control and safer than regular fluids. This is because in neurologic diseases delayed triggering of the pharyngeal swallow with or without premature bolus loss may often result in subglottic aspiration before or during the swallow. For this reason thickening fluid viscosity is believed to reduce the risk of aspiration. Recent studies highlight serious considerations in prescribing modified food to patients with dysphagia in terms of long-term efficacy, nutrition, and compliance. It is documented that older people on texture-modified diets have a lower calorie and protein intake than those on a normal diet.[70] It has been shown that over 20% of patients are noncompliant to the prescribed management of their dysphagia.[71] The high proportion of noncompliancy to modified food can be partly explained by the 184 Byung-Mo Oh and Nam-Jong Paik

fact that eating food with modified texture is associated with a lower level of perceived quality of life.[72] There are a few reports regarding the efficacy of the long-term use of texture- modified food in patient populations. A recent randomized clinical trial on the efficacy of modified food in patients with dementia or Parkinson's disease reported an immediate effect of thickened liquid in preventing aspiration.[73] The study, however, failed to demonstrate any significant improvement in long-term outcome measures.[36] Future studies will be required to ascertain the long-term efficacy and safety as well as compliance on modified food. At present, individually tailored management derived from careful clinical evaluation as well as videofluoroscopic examination is required.

E. Tube feeding and Parenteral Nutrition Despite every effort a rehabilitation team makes, safe and sufficient oral intake cannot be achieved in some patients. A high risk of repetitive aspiration and poor endurance render patients to require a non-oral route of intake. For short-term use, nasogastric tube feeding and parenteral nutrition can be considered. For patients who need long-term solution, gastrostomy feeding can be a good option.

i. Nasogastric tubes For short-term use (usually shorter than 6 weeks), a soft, small-bore nasogastric feeding tube (NGT) can be placed.[25] Because many patients are still able to eat even with NGT in place, swallowing rehabilitation can be started concurrently with nutritional supplement using NGT. Although the NGT is the most common route of nasoenteral feeding, orogastric, nasoduodenal or nasojejunal feeding can be used in patients with special needs. Potential complications are local irritation, ulceration of the nasal and esophageal tissues and subsequent stricture formation, and aspiration from reflux.[74] ii. Feeding gastrostomy and jejunostomy Long-term tube feeding usually requires a gastrostomy tube. A typical procedure of percutaneous endoscopic gastrostomy (PEG) insertion can be performed within 30 minutes. Surgical gastrostomy and jejunostomy can also be considered when endoscopic and radiologic insertion is technically challenging. Complications with this procedure include irritation around the site of insertion, peritoneal leak, balloon migration, and obstruction of the pylorus.[65, 74] Tubes for gastrostomy feeding can be removed if patients achieve their abilities to eat safe orally. Although PEGs has largely replaced NGTs for nutritional support of patients with head and neck cancer undergoing chemotherapy or radiation therapy, the issue of whether PEGs are superior to NGTs in other dysphagic patients has remained controversial. Results from a prospective clinical trial suggest that early PEGs shows superior outcome of case fatality, but worse functional outcome in patients with head and neck cancer.[75] At present, there is little evidence justifying the routine use of PEGs in this patient population. iii. Intermittent oroesophageal tube feeding Management of Swallowing Difficulty in Pharyngeal Diseases 185

Orogastric tubes are often used in infants with feeding difficulties. Intermittent oroesophageal tube feeding (IOE) has been introduced as an alternative to nasogastric tube feeding.[76] Patients who are reluctant to nasogastric or gastrostomy tubes can use this method. Important prerequisites for the use of IOE are a reduced or absent gag reflex and learning ability. A large-bore (e.g. 14F) urethral tube is commonly used. IOE is relatively contraindicated in patients with a sensitive gag reflex, esophagitis, Zenker diverticulum, or large cervical osteophytes. Advantages of IOE are a faster speed of feeding and training effect of the IOE per se. Despite successful clinical use, IOE has not yet been evaluated in well-designed clinical trials. iv. Parenteral nutrition Parenteral nutrition refers to nutritional supply directly into the bloodstream via central or peripheral veins. Generally enteral feeding is preferred to parenteral nutrition because enteral nutrition has an advantage in maintaining the digestive, absorptive, and immune function of the gastrointestinal tract. There are well-known complications with the use of central total parenteral nutrition including mechanical and metabolic complication, venous thromboembolism, infection, and hepatobiliary complications. Long-term parenteral nutrition can be given through an implantable subcutaneous port.[25]

5. Preventive Approach

A. Range-of-motion exercise Head and neck cancer patients quite often experience extensive scar formation after surgery. Early initiation of range of motion exercise for the jaw, tongue, lips, and larynx in the first 3 months after surgery is advocated.[77] In addition, soft tissue fibrosis can ensue after radiation therapy. To prevent disability caused by the fibrosis, early implementation of range of motion concurrently with radiation therapy should be encouraged. A protocol of five to ten sessions daily with a session consisting of five to ten repetitions of one-second holding in a stretched position is recommended. This protocol seems to be inadequate to achieve a stretch effect compared to well-established stretching protocols for the limbs. The optimal frequency and duration has not been evaluated extensively. Patients are instructed to flex, extend, tilt, and rotate the neck to the best of their ability. For the jaw, opening the mouth and thrusting the jaw to the lateral side can be performed. Instead of putting too much emphasis on direct mobilization of the larynx to the stretched position, indirect maneuvers such as the Mendelsohn maneuver and falsetto voice production can accomplish considerable laryngeal elevation. The complex array of muscle fibers enables the tongue to move freely in three-dimensional space. Extension, lateralization, elevation, and retraction are the basic movement patterns to be practiced. Unlike the other movements, the tongue retraction cannot be easily demonstrated to the patient, which warrants a special strategy to achieve, reinforce, and provide feedback. Simulating yawning or gargling is a common technique used in promoting tongue retraction. VFS is also useful to verify the effect of above mentioned maneuver on producing tongue retraction. Education using an 186 Byung-Mo Oh and Nam-Jong Paik anatomical model and video clips can help patients to understand the modus operandi in the movement of tongue and soft palate.

During bed rest, disuse atrophy is usually more evident in the lower extremities than in the upper limbs.[78] Inactivity has profound effect not only on the neuromuscular system of the limb musculature but also of the axial muscles. A recent investigation showed that complete inactivity for a several-day duration results in obvious atrophy in human diaphragm myofibers.[79] Considering that swallowing movement can be completely abolished in the critically-ill patient during several days of mechanical ventilation and tube feeding, it is no wonder that dysphagia is quite a common in patients with critical-illness in their convalescing phase. Although the muscle is easily atrophied in response to a very short duration of inactivity, the recovery requires tremendous effort and time.[27] Therefore, conscious effort to swallow the saliva with or without presentation of food tastes should be recommended as early as possible to prevent this devastating cycle of functional decline.[37]

Conclusion

Because loss or impairment of swallowing function can affect multiple facets of the patient‘s life, rehabilitation of swallowing difficulty involves a multidisciplinary team approach. Rehabilitation includes restorative approaches, compensation, and psychological support. Cautious evaluation of the pathophysiology and implementation of a creative therapeutic strategy inevitably requires thorough understanding of the anatomy, physiology, and the physiologic effects of individual therapy. High incidence of preventable cause of dysphagia in medically-ill patients warrants early intervention. Future studies will be required to demonstrate the long-term efficacy of therapeutic strategies currently being used.

References

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Chapter VII

Infections of the Pharynx

Mustafa Gul* Department of Microbiology and Clinical Microbiology, Faculty of Medicine Kahramanmaras Sutcu Imam University, Yorukselim Mah., Gazi Mustafa Kuscu Cad., No: 32, PK: 46050 Kahramanmaras – Turkey.

Abstract

The pharynx is a common site of infection. The etiology is usually infectious, with 40-60% of cases being of viral origin and 5-40% of bacterial origin. A number of different viruses can infect the human throat. The most common viral causes of pharyngitis are adenovirus and Epstein-Barr virus however others include, influenza virus, herpes simplex virus, rhinovirus, coronavirus, respiratory syncytial virus and parainfluenza virus. The primary cause of bacterial pharyngitis is Streptococcus pyogenes, however others include, Corynebacterium diphtheriae, Arcanobacterium haemolyticum, Neisseria gonorrhoeae, Chlamydophila pneumoniae and Mycoplasma pneumoniae. Some cases of pharyngitis are caused by fungi such as Candida albicans. Infection of the pharynx is associated with pharyngeal pain. Inspection of the pharynx reveals that affected tissues are red and swollen. Depending on the causative microorganism, enlarged and tender nasopharyngeal lymph nodes, vesicles, inflammatory exudates, mucosal ulceration, headache and aching muscles and joints may be observed. The diagnosis of viral pharyngitis is made by examining the throat and serological tests. The gold standard for diagnosis of bacterial pharyngitis is culture on agar. The primary purpose of a throat culture is to isolate and identify organisms from the pharynx that cause infection. The specimen for pharynx culture is obtained by wiping the patient's throat with a cotton swab. Throat cultures should be taken before the patient is started any antibiotic medications. An accurate diagnosis is essential to prevent unnecessary use of antibiotics.

* Corresponding author: Tel: +90 344 2212337 / Ext.448, Fax: +90 344 2212371, GSM:+90 532 3745791, E-mail: [email protected]. 194 Mustafa Gul

Introduction

The pharynx is one of the most common sites of infection in the human body. Also acute pharyngitis is the most common upper respiratory tract infection affecting both children and adults. Acute pharyngitis is an inflammatory syndrome of the pharynx caused by several different microorganisms. Most cases are of viral etiology and occur as common cold and influenzal syndromes. Bacterial infection is the other common cause of pharyngitis. It is important to differentiate bacterial from viral pharyngitis because of the response of bacterial infection to antimicrobial therapy and the ineffectiveness of antibiotic therapy in viral infections. This chapter reviews common causes of pharyngitis, relevant available clinical information, appropriate laboratory tests, and recommended treatment guidelines.

Etiology

A number of different viruses can infect the pharynx. The most common viral causes of pharyngitis are adenovirus and Epstein-Barr virus (EBV), however others include, rhinovirus, coronavirus, influenza virus, coxsackie virus, herpes simplex virus, respiratory syncytial virus and parainfluenza virus. Other respiratory viruses each accounts for a small proportion of the cases. Acute retroviral syndrome caused by human immunodeficiency virus (HIV) has joined viral infections associated with acute pharyngitis [1]. The primary cause of bacterial pharyngitis is Streptococcus pyogenes, however others include, Corynebacterium diphtheriae, Arcanobacterium haemolyticum, Neisseria gonorrhoeae, Yersinia enterocolitica, Treponema pallidum, Francisella tularensis, Chlamydophila pneumoniae and Mycoplasma pneumoniae. Some cases of pharyngitis are caused by fungi such as Candida albicans [2]. Nearly 8-10% of all cases of pharyngitis in adults and 20-25% in children are due to S.pyogenes (group A beta-hemolytic streptococci). Non-group A beta-hemolytic streptococci is not very important as a cause of pharyngitis. Group C streptococci have been associated with endemic pharyngitis in college students and other adult populations [3,4]. In addition, beta- hemolytic streptococci of groups C and G have been associated with foodborne outbreaks of pharyngitis. [5, 6, 7, 8]. Other non group A beta hemolytic streptococci, except group G, have not been definitely implicated as a cause of endemic pharyngitis [9, 10, 11, 12, 13].

Epidemiology

Pharyngitis is common all over the world. According to the results of epidemiological research, most cases of pharyngitis occur during the colder months of the year. Adenoviruses have a worldwide distribution. Adenovirus infections can occur throughout the year. Outbreaks of adenovirus-associated respiratory disease have been more common in winter, spring, and early summer. All ages are susceptible to adenovirus infection, but infection usually occurs during childhood [14, 15]. EBV Infections of the Pharynx 195 infections are seen in very young preschool children aged 1-6 and adolescents and young adults aged 14–20. In developing countries, 80-90% of the adult population have been infected by the virus. EBV primarily spreads via passage of saliva, but is not a particularly contagious disease [16, 17]. Rhinovirus, coronavirus and influenza virus infections are common in all age groups, they occur throughout the year worldwide. Especially, infections of rhinovirus occurs in fall and spring; coronaviruses are found most often in winter. Influenza appears as epidemics between December and April. Bacterial pharyngitis occurs during the respiratory disease season, with peak rates of infection in fall, winter, and early spring.

Pathophysiology

Pharyngitis is an inflammation of the pharynx that can lead to sore throat and difficulty swallowing. Etiologic agents are passed through person to person contact, most likely via droplets of nasal secretions or saliva. Symptoms often manifest after an incubation period ranging from 1 to 5 days. Outbreaks of pharyngitis may occur in households or classrooms, and infrequently may be linked to food or animal sources. Pharyngeal complaints are present in up to 80% of people with parainfluenza virus illness and in approximately 50% of people with adenovirus or type A influenza illness [18]. Symptoms of sore or scratchy throat occur in approximately 50% of people with rhinovirus colds and in 20% to 70% of people with colds due to conventional coronaviruses [19, 20, 21, 22]. Other viral respiratory illnesses with pharyngitis occur with EBV, herpes simplex virus, coxsackievirus, and cytomegalovirus infections [23]. The pathogenesis is different for the various organisms. Nasal epithelial biopsies obtained from volunteers with experimental rhinovirus infections have shown little or no evidence of viral cytopathic effect [24, 25]. However, it has been noted that bradykinin and lysylbradykinin are generated in the nasal passages of persons with experimental and natural rhinovirus colds [26, 27]. These inflammatory mediators are potent stimulators of pain nerve endings. Also, volunteers given experimental intranasal exposure with bradykinin have developed symptoms of sore throat [28]. There is evidence that direct invasion of pharyngeal mucosa occurs with other respiratory virus infections, such as those caused by adenovirus and coxsackievirus. Edema of the pharyngeal mucous membrane occurs with viral infections. An inflammatory exudate and pharyngeal lymphoid hyperplasia may exist in adenovirus and EBV infections. Also, mucosal ulceration and vesiculation may occur with herpes simplex virus and coxsackievirus infections. In streptococcal pharyngitis, there is an intense inflammatory response characterized by marked erythema and edema of the fauces and uvula, and frequently by a grayish yellow tonsillar exudate. A fibrous pseudomembrane containing necrotic epithelium, leukocytes, and bacterial colonies develops on the epithelial surface in diphtheria [29].

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Viral Infections

Adenovirus

Adenovirus is a common cause of viral pharyngitis. It is indicated clinically as an upper respiratory infection with fever, rhinorrhea, cough, and sore throat, usually more severe than in the common cold. The pharynx is erythematous and frequently may have exudates that mimic streptococcal pharyngitis [30]. A distinctive syndrome associated with adenovirus infection in children is pharyngoconjunctival fever. The disease occurs in outbreaks and is characterized by rhinitis, pharyngitis, conjunctivitis, high fever, and cervical adenitis. Although adenoviral infections commonly occur in winter months, pharyngoconjuntival fever has been implicated in outbreaks in summer camps and associated with contaminated swimming pools and ponds [31]. Several types of adenovirus also have been implicated in outbreaks of influenza-like illnesses with sore throat, rhinorrhea, and tracheobronchitis, known as acute respiratory disease of army recruits [32, 33]. These infections are self limited, and symptomatic treatment alone is recommended.

Epstein-Barr Virus

Infectious mononucleosis (IM) or ―glandular fever‖ is caused by the EBV. The virus is present in the oropharyngeal secretions of patients who have IM and spreads by person-to- person contact. Infection with EBV is frequent in childhood but usually asymptomatic. Clinical manifestations are more common when the infection is acquired in adolescence or young adulthood. Thus, most cases of IM occur between 15 and 24 years of age. Symptoms develop after an incubation period of 4 to 7 weeks. Following a 2- to 5-day prodromal period of chills, sweats, feverishness, and malaise, the disease presents with the classic triad of severe sore throat accompanied by fever as high as 38°C to 40°C and lymphadenopathy. Lymphadenopathy is bilateral, particularly posterior cervical, but can involve axillary and inguinal areas. Some patients have a rash of variable morphology, but use of ampicillin or amoxicillin provokes a pruritic maculopapular eruption in the majority of patients. Splenomegaly occurs in almost half of the patients and also hepatomegaly is present in 10% to 15% of patients. This classic clinical presentation of IM occurs in most of the children and young adults. Older adults may not present pharyngitis or lymphadenopathy, and disease can be manifested only with fever and more prominent hepatic abnormalities [34]. In most cases, the diagnosis is easily confirmed. Initial diagnostic studies should include throat culture and a serologic test for the presence of heterophile antibodies. Spot and slide tests allowing rapid screening are commercially available. When combined with an appropriate clinical presentation, a positive rapid test for heterophile antibodies can be considered diagnostic of IM. False-negative tests can occur especially in children, older adults, and in the early stages of the disease. On the other hand, nearly 10% of patients who have a classic mononucleosis syndrome have negative tests for heterophile antibodies. In these patients, EBV specific antibodies should be assayed. The most useful of these for general clinical purposes is the IgM antibody to viral capsid antigen. This antibody is present at clinical presentation and Infections of the Pharynx 197 persists for 4 to 8 weeks. Antibody to Epstein-Barr nuclear antigen first appears 3 to 4 weeks after the onset and persists for the whole life [35]. Infections of EBV are predominantly a self-limited disease, and studies have failed to detect any benefit of using antiviral agents. Most symptoms resolve within 3 weeks of onset. Physical activity is adapted to patient tolerance. Because of the risk of splenic rupture, contact sports and heavy lifting should be avoided until the spleen returns to normal size, usually in approximately 3 to 4 weeks. The use of corticosteroids has been studied in clinical trials, but no clear benefit has been demonstrated [36]. Steroids may be useful in the management of severe complications such as airway obstruction, hemolytic anemia, and severe thrombocytopenia.

Rhinovirus

Rhinovirus is produced primarily in the nose and pharynx. The incubation period of rhinovirus colds is generally 16 to 20 hours. The most prominent symptoms include nasal discharge, nasal congestion, sore throat, sneezing, and cough. The clinical manifestations of common cold are so typical that the diagnosis is usually made by the patient. Serologic diagnosis of rhinovirus infection is not practical because of the numerous antigenic types. Treatment of the patients with an uncomplicated common cold is symptomatic. Regular hand washing and care to avoid contamination of the enviroment with nasal secretions may help to prevent the spread [37].

Coxsackievirus

Outbreaks of coxsackievirus infections most commonly occur in summer and fall. Coxsackieviruses can spread from person to person, usually through unwashed hands and surfaces contaminated by feces, where they can live for several days. These viruses can also cause several different symptoms that affect different body parts. Herpangina most often is caused by coxsackie A and is most frequent in infants or toddlers. It usually presents acutely with fever, headache, vomiting, odynophagia, sore throat, a vesicular enanthem, and diffuse pharyngeal erythema. The oral lesions consist of 1- to 2-mm gray-white papulovesicles that progress to ulcers on an erythematous base and may be present on the soft palate, uvula, and anterior tonsillar pillars [38]. Hand-foot-and-mouth disease also is caused by coxsackie A. It is characterized by a febrile vesicular stomatitis with associated exanthema. The lesions are similar to those seen in herpangina, but there is an associated peripheral rash involving hands and feet. The treatment of coxsackie diseases are symptomatic and these infections are self limited.

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Herpes Simplex Virus

Herpes simplex virus (HSV) infection occurs in both primary and recurrent forms. It is transferred through direct contact with mucus or saliva. The clinical manifestations and course of HSV depend on the anatomic site of the infection, the age and immune status of the host. Gingivostomatitis and pharyngitis are more common clinical manifestations of primary HSV type 1 infection. These infections are usually seen in children and young adults. Various studies have documented primary HSV-1 infection as a cause of pharyngitis in college students [39, 40]. Although the characteristic presentation consists of small vesicles and ulcerations in the posterior pharynx, HSV also may produce pharyngeal erythema and exudates. Lesions may extend to the palate, gingiva, tongue, lip, and face. Clinical symptoms and signs include fever, malaise, myalgias, anorexia, irritability, and cervical adenopathy. HSV can be isolated from almost all lesions. Laboratory confirmation of HSV infection is best performed by isolation of the virus in tissue culture or demonstration of HSV antigens in scrapings from lesions. Identification can be made in a variety of cell culture systems within 48 hours after inoculation. Treatment of HSV infection with antiherpetic medication is efficacious in reducing the duration of signs and symptoms as well as viral shedding. Acyclovir and famcyclovir are all useful in treating HSV infection.

Human Immunodeficiency Virus

Pharyngitis occurs in patients infected with HIV as part of the acute retroviral syndrome. Fever, maculopapular rash, sore throat, lymphadenopathy, myalgia, arthralgias, and mucocutaneous ulcerations are the signs of the syndrome [1, 41, 42, 43]. A nonexudative pharyngitis is present more than half of the patients. Other oropharyngeal findings include ulcers and thrush. Ulcers are usually in the inner lips and in the floor of the mouth, but tonsils, soft palate, and uvula also may be involved. The clinical findings such as fever, pharyngitis, and lymphadenopathy may simulate IM. Acute retroviral syndrome can be differentiated from mononucleosis, however, by its more acute onset, the absence of exudate or prominent tonsillar hypertrophy, the frequent occurrence of rash and the presence of oral ulcerations [44]. It is important for the clinician to recognize that the ELISA/Western blot test detects antibodies to the HIV virus. The ELISA results commonly used to diagnose HIV-1 infection are negative in the first 3 to 4 weeks after infection and therefore are not useful in this setting. Tests for p24 antigen or preferably, quantitative assays for plasma HIV RNA by branched chain DNA or PCR should be performed. The viral load can be anticipated to be very high during this acute phase of infection. HIV antibody test always should be performed later in time to confirm the diagnosis. Treatment of acute retroviral syndrome with highly active antiretroviral medication has been controversial, current recommendations consider the use of antiretroviral medications in the setting of acute HIV infection to be optional [45]. Potential benefits of antiretroviral therapy in acute HIV would be to decrease the severity of acute disease and to decrease viral replication. Studies have demonstrated improvement of laboratory markers of disease progression when highly active antiretroviral therapy is used in acute HIV infection Infections of the Pharynx 199

[46, 47]. These results would suggest a decrease in progression and transmission of the disease.

Bacterial Infections

Corynebacterium diphtheriae

Pharyngeal diphtheria is caused by Corynebacterium diphtheriae. Although diphtheria is relatively uncommon in developed countries because of the widespread vaccination of susceptible individuals, it is a cause of significant morbidity and mortality in developing countries [48, 49]. The infection is prevented by widespread immunization of at risk population with diphtheria toxoid. Pharyngeal diphtheria is primarily transmitted among humans via direct contact or sneezing or coughing [50]. Carriage of the organism on the skin and asymptomatic carriage of the organisms in the upper respiratory tract are common sources of transmission to other susceptible individuals [51]. During an incubation period of 2-7 days, the organism multiplies locally in the posterior nasopharynx and pharynx. During this period, there is an accumulation of organisms, fibrin, and inflammatory cells to produce the characteristic diphtheric pseudomembrane, which may eventually cover the pharynx, larynx, and tonsils. These pseudomembranes may lead to airway obstruction resulting in death. The toxin is also responsible for severe cardiac and neurologic complications [52]. Cardiac complications manifested as myocarditis with cardiac dysfunction ocur in 15% to 25% of cases, usually when the pharyngeal manifestations are improving. Neurologic complications can also occur and are related directly to the severity of the primary infection, the immunization history, and the time between the onset of symptoms and initiation of treatment. The diagnosis of diphtheria requires a high index of suspicion and specific laboratory techniques. For the isolation of C. diphtheriae, swab specimens are obtained from the oropharynx, nasopharynx, or cutaneous lesions. Swabs should be used to sample multiple, inflamed areas of the pharynx. If a pseudomembrane is present, swab specimens from beneath the membrane should be collected. Swab specimens may be sent to the laboratory in a routine semisolid transport medium. These swabs are inoculated onto a sheep blood plate, and an agar medium containing cystine and potassium tellurite. For the cystine tellurite medium, laboratories should use cystine tellurite blood agar or modified Tinsdale agar for the recovery of C.diphtheriae. C. diphtheriae will grow as black colonies with metachromatic granules on Tinsdale‘s selective medium. But definitive diagnosis requires demonstration of toxin production by immunoprecipitation, immunochromatography or molecular methods. Many laboratories that perform toxigenicity tests use the modified Elek immunoprecipitation procedure [53]. Several other methods, including enzyme immunoassays and reverse passive latex agglutination tests have also been developed for the detection of toxin production by C.diphtheriae [53, 54, 55, 56]. Molecular methods have also been developed for detection of toxin production by C.diphtheriae. Most polymerase chain reaction (PCR) methods have been directed at the tox gene, using primers that flank sequences corresponding to the biologically active toxin fragment A [57, 58, 59]. These methods have been used for toxin detection in pure cultures of C.diphtheriae and directly in clinical specimens. 200 Mustafa Gul

Treatment of diphtheria includes diphtheria antitoxin and antibiotics. The therapeutic diphtheria dose and mode of administration are recommended by The Committee on Infectious Diseases of the American Academy of Pediatrics according to the duration and extension of the disease [60]. Antibiotic therapy has benefits such as; termination of toxin production, amelioration of the local infection, and prevention of spread of the organism to uninfected subjects. Although several antibiotics are effective in vitro, only penicillin and erythromycin have been studied in controlled trials. Both drugs are equally effective in resolving fever and local symptoms, and the time of disappearence of membrane. Patients should be maintained in strict isolation throughout the therapy and, following the therapy, should have two consecutive negative cultures at 24 hour intervals to document eradication of the organism [60].

Neisseria gonorrhoeae

Neisseria gonorrhoeae causes pharyngeal infection, but it is uncommon. Pharyngeal gonococcal infection is seen in homosexual and bisexual men and heterosexual women who acquire the infection by engaging in orogenital sexual contact with an infected partner. Pharyngeal gonorrhea may also be seen occasionally in heterosexual men. More than 90% of oropharyngeal gonococcal infections are asymptomatic [61]. Also according to a recent study in San Francisco, there was no association between the presence of N. gonorrhoeae and pharyngeal symptoms [62]. Most cases resolve spontaneously, pharyngeal infection probably is less transmissible than rectal or genital gonorrhea, and the pharynx rarely is the only infected site. Pharyngeal infection can be symptomatic and sometimes is the source of transmission to sex partners, especially among men who have sex with men, or of systemic dissemination of N.gonorrhoeae [63,64]. When symptomatic oral infection does occur, pharyngitis, tonsillitis, gingivitis and glossitis are common manifestations. Sore throat with an erythematous pharynx, bilateral tonsillar enlargement, at times with grayish-yellowish exudate, and occasionally with cervical lymphadenopathy have been reported [65]. For the diagnosis; microscopy is both insensitive and nonspecific for detection of pharyngeal gonococcal infection and is not recommended. Moreover there is no clinically useful serological test. The diagnosis should be confirmed by culture on antibiotic-containing selective medium, such as modified Thayer-Martin medium. Recommendation for the treatment of gonococcal infection, either a single 125mg intramuscular dose of ceftriaxone or a single 400mg oral dose of cefixime is effective for infection of all mucosal sites, with cure rates that exceed 90% for pharyngeal infection and both regimens are safe and effective in pregnant women [66, 67].

Arcanobacterium haemolyticum

Arcanobacterium haemolyticum was first isolated by MacLean et al. in 1946 from American soldiers and Pacific Islanders with pharyngeal and skin infections in the South Pacific [68]. A. haemolyticum has been increasingly identified as a cause of exudative Infections of the Pharynx 201 pharyngitis in humans, clinically similar to that caused by beta hemolytic streptococci [69,70,71]. Typically, the infection has been recognized in children, adolescents, and young adults and is associated with a diffuse, pruritic, erythematous maculopapular skin rash on the extremities and trunk. In studies, A. haemolyticum has not been isolated from healthy control populations, but has been isolated from 2.5% of a symptomatic young adult population. Pharyngeal exudates have been presented in 54% of patients, cervical lymphadenopathy in 41%, and rash in 44% [72,73]. A. haemolyticum is more readily identified on rabbit or human blood agar than on sheep blood agar. This organism is usually susceptible to all classes of antimicrobial agents, including penicillins, cephalosporins, macrolides, and vancomycin, with resistance to trimethoprim-sulfamethoxazole being a consistent finding. Some isolates may be resistant to tetracyclines, the macrolides, clindamycin, and ciprofloxacin [74,75,76].

Yersinia enterocolitica

Yersinia enterocolitica is widely distributed in the world and can be isolated from multiple environmental sources, including fresh water, contaminated foods, and a wide range of wild and domestic animals[77]. Y. enterocolitica is a pleomorphic Gram-negative bacillus in the family of Enterobacteriaceae. It is non lactose fermenting, urease positive organism that grows at a wide range of temperature; it is motile at 25 °C but not at 37 °C. The organism adheres to and penetrates the ileum, causing terminal ileitis, lymphadenitis, and acute enterocolitis, with secondary manifestations of polyarthritis, erythema nodosum and less commonly, endocarditis and septicemia [78, 79, 80]. Y. enterocolitica is relatively recently recognized cause of pharyngitis. Exudative pharyngitis is a part of the spectrum of illness caused by Y. enterocolitica. In the large Y. enterocolitica enteritis outbreak in the USA, 8% of patients presented with acute pharyngitis and fever, without accompanying diarrhea [81]. In other study; fever, prominent cervical lymphadenopathy, and abdominal pain with diarrhea have been reported [82]. Y. enterocolitica is isolated from pharyngeal exudates, depending on the clinical syndrome. It grows on McConkey and CIN agar. Moreover, serologic tests are useful in diagnosing yersinia infections provided sera are appropriately absorbed. Agglutination tests, ELISAs, and immunoblotting tests are used. PCR and immunohistochemical staining procedures are experimental. In vitro antibiotic susceptibility test of Y. enterocolitica is not reliable, and the administration of broad spectrum cephalosporins in combination with an aminoglycoside appears effective for most extraintestinal infections [83].

Francisella tularensis

Francisella tularensis is a gram negative coccobacillus pathogen primarily in animals and sometimes in humans. Reservoirs of the bacterium in nature include rabbits, rodets, deer, and domestic animals such as sheep, cattle, swine, and horses. F. tularensis is transmitted among animals by ticks and biting flies such as deer flies. Infections in humans are most commonly acquired by bites from infected ticks, and mosquitoes, or by direct contact with 202 Mustafa Gul blood or internal organs of infected animals [84]. Contaminated water is also an important source of F. tularensis in the environment, and infections in humans have occurred following ingestion of water from wells in which infected animal carcasses have been found [85]. The clinical manifestations of F. tularensis infection depend on the virulence of the particular organism, the extent of systemic involvement, and the immune status of the host. After infection, there is an incubation period of 2 days to 3 weeks, followed by the acute onset of fever, headache, sore throat, chills, anorexia, fatigue, and malaise. Tularemia can be divided into six major forms: ulceroglandular, glandular, oculoglandular, pharyngeal, typhoidal, and pneumonic. Pharyngeal tularemia is the result of primary invasion through the oropharynx. The source may be contaminated foods or water. Pharyngeal tularemia, which represents 0% to 12% of cases overall, has been seen with increasing frequency in Japan, and may predominate in outbreaks [86, 87]. Usually, children have been involved more often than adults, and several family members may be affected simultaneously [88]. In pharyngeal tularemia, the patient‘s predominant complaint typically is of fever and severe throat pain. Exudative pharyngitis is the rule, and one or more ulcers may be seen. Cervical and retropharyngeal adenopathy may be present, occasionally with bilateral involvement. The differential diagnosis includes streptococcal pharyngitis, diphtheria, Vincent‘s disease, adenoviral infection, and infectious mononucleosis. F. tularensis may be isolated from pharyngeal specimens. The specimens should be kept at 4-8 °C until processing. F. tularensis has also been isolated from lymph node aspirates and biopsies, primary ulcers, blood, bone marrow, sputum, and tissue biopsies. Positive blood cultures have been found in patients with typhoidal, pneumonic and pharyngeal tularemia [89, 90, 91]. Serological tests are the most common method for the diagnosis of tularemia. The antibody response to F. tularensis infection is influenced to some degree by the clinical form of the disease, and may have an impact on serologic results depending on the method used [92]. Moreover, the rapid diagnosis of F. tularensis infection should be a more urgent goal as a result of its potential use as an agent of bioterrorism. The drug of choice for the treatment of all forms of tularemia except meningitis is streptomycin, with gentamycin being an alternative agent [93, 94].

Chlamydophila pneumoniae

Chlamydiaceae are obligate intracellular bacteria that have a unique biphasic developmental cycle. Chlamydiae have cell walls and replicate by binary fission. The small, dense elementary body is the metabolically inactive infectious form of the organism. Chlamydophila pneumoniae can persist in tissues for prolonged periods of time after initial infection. C. pneumoniae is a cause of pharyngitis. It has been detected in pharyngeal specimens from persons without concurrent respiratory symptoms. In one study of schoolchildren in Germany, C. pneumoniae was detected by PCR in throat swabs from 5.6% of children tested [95]. On the other hand, detection of C. pneumoniae DNA in throat swabs from adults has also been reported [96]. The incubation period of infection related to C. pneumoniae is about three weeks, which is longer than the incubation period of many other pharyngeal pathogens. Infections of the Pharynx 203

The laboratory diagnosis of C. pneumoniae infections is complicated by the difficulty of culture. Most infections are diagnosed serologically. If C. pneumoniae infection is strongly suspected, consideration can be given to use of more specific course of therapy. Erythromycin and tetracycline are active in vitro against C. pneumoniae and have classically been recommended as first line therapy for suspected C. pneumoniae infections.

Mycoplasma pneumoniae

Mycoplasma pneumoniae is known as a cause of lower respiratory tract infections; it also can be found in the throats of patients who have symptomatic pharyngitis and of asymptomatic carriers. Even though this agent probably causes some cases of acute pharyngitis, either as primary pathogen or copathogen, the frequency with which this occurs is still unclear. The pharyngeal manifestations that have been described include tonsillar enlargement, erythema, and, less often, exudate with cervical adenopathy. M. pneumoniae is not a common cause of isolated pharyngitis in the adult population. In a recent study, 133 children who had acute tonsillopharyngitis were tested for M pneumoniae with acute and convalescent phase titers and PCR on nasopharyngeal aspirates. Thirty-six of the children (27%) had serologically confirmed acute M. pneumoniae infection [97]. In the recent years for diagnosis of M. pneumoniae infections, PCR performed on a throat swab specimen serves as a specific and rapid diagnostic method [98, 99, 100]. The treatment of M. pneumoniae pharyngitis is macrolides and tetracyclines. On the other hand, antimicrobial therapy is not necessary for mycoplasmal upper respiratory tract infection, and the mycoplasmal etiology of this syndrome probably most often goes undiagnosed.

Streptococcus pyogenes

Streptococcus pyogenes, or group A streptococcus (GAS), is a facultative, Gram positive coccus which grows in chains and causes numerous infections in humans including pharyngitis, tonsillitis, rheumatic fever, post-streptococcal glomerulonephritis, scarlet fever, cellulitis, erysipelas, necrotizing fasciitis, myonecrosis and lymphangitis. GAS require complex media containing blood or blood products, grow best in an environment of 10% carbon dioxide and produce pinpoint colonies on blood agar plates which are surrounded by a zone of complete (beta) hemolysis. Pharyngitis caused by GAS is the most common bacterial pharyngitis diagnosed in developed countries. Streptococcal pharyngitis affects school age children, especially those 5–12 years old, but children and adults of all ages can be infected with GAS. The classical patient with acute streptococcal pharyngitis is a school-age child with sudden onset of fever and sore throat in the late winter or spring. Headache, nausea, malaise, abdominal pain, and vomiting occur frequently. Cough, rhinorrhea, stridor, conjunctivitis, and diarrhea are distinctly unusual. The pharynx is erythematous. Petechiae may be seen on the soft palate. Tonsils are red and enlarged with patchy exudates. The papillae of the tongue may be swollen and red. Tender, enlarged anterior cervical nodes are common. Any of these ‗classic‘ 204 Mustafa Gul symptoms and signs may be absent in a particular patient; reliable diagnosis requires swabbing the throat for culture or a group A carbohydrate antigen detection test. Children less than 3 years old can develop culture-positive streptococcal pharyngitis. Culture of the nares may be more sensitive than throat culture in this age group [101]. Exposure to someone with the disease at home, such as a sibling, is a risk factor. Cough, coryza, and hoarseness occur more frequently than they do among older children [102, 103]. Streptococcal sore throat is often described as a raw feeling, exacerbated when liquids are swallowed. Dysphagia can be so severe that the child refuses to eat or drink and some children may drool rather than swallow their saliva. Ear pain may occur with the sore throat. Many patients complain of abdominal pain, nausea, and vomiting. However, diarrhea does not occur. Headache is often present at the onset of the illness, commonly occurring with the nausea and vomiting. Mental status is normal and there are no complaints of photophobia or posterior neck pain. Clinical manifestations of streptococcal pharyngitis in adults are quite similar to those in children. Adults with this disease are likely to have had recent exposure to persons with streptococcal infection and to manifest pain on swallowing and myalgias. They are also less likely to complain of cough, rhinorrhea or itchy eyes than patients whose throat cultures are negative for GAS [104, 105, 106]. Abdominal pain and vomiting are rare in adults[107]. Signs associated with adult streptococcal pharyngitis include pharyngeal erythema, pharyngeal or tonsillar exudates, tonsillar swelling, tender and swollen anterior cervical lymph nodes and fever. There are numerous studies on S. pyogenes pharyngitis diagnosis in the literature, but there are only a few which describe clinical prediction rules for S. pyogenes pharyngitis in children who are at highest risk for sequelae. In children, there are limited evaluations of clinical prediction rules. The earliest studies done on is subject were those by Breese-Disney and Stillerman-Bernstein who correlated clinical findings with culture results [107, 108]. However, they selected cases for study on the basis of clinical features suggesting GAS pharyngitis. Kaplan et al. studied 624 children less than 15 years of age with uncomplicated pharyngitis and compared clinical features both with throat culture and antibody rise [109]. He found that 35% of cases were GAS culture positive, but only 43% of these showed an antibody rise, indicating a true infection prevalence of 15%. The World Health Organization Acute Respiratory Infections treatment program suggests that, in the absence of other guidelines for children under 5 years of age, acute streptococcal pharyngitis should be suspected and presumptively treated when pharyngeal exudate plus enlarged and tender cervical lymph nodes are found [110]. When these recommendations were evaluated in a prospective study, the guidelines were shown to be highly specific, but not very sensitive. A practice guideline for the diagnosis of acute pharyngitis in adults is endorsed by the American College of Physicians-American Society of Internal Medicine, Centers for Disease Control and Prevention, and American Academy of Family Physicians [111, 112]. This guideline shows four clinical criteria: presence of tonsillar exudates, presence of swollen tender anterior cervical nodes, lack of cough, and history of fever [113]. These four characteristics have been reported to be independently associated with the likelihood of a positive throat culture for group A streptococci [114]. This algorithm provides three alternative management strategies: empirical antimicrobial treatment of adults with at least Infections of the Pharynx 205 three of four clinical criteria and nontreatment of all others, empirical treatment of adults with all four criteria, and performance of a GAS rapid antigen diagnostic test (RADT) in patients with two or three clinical criteria and treatment of those with positive tests [112]. The classical method for establishing the actual presence of a GAS in the throat is the throat swab. Diagnostic sensitivity is dependent on a number of variables including the adequacy of the swabbing technique, conditions operating for transportation of the swab, the methodology employed to detect a GAS and the interpretation of the results obtained including consideration of any recent antimicrobial exposure. The recommended procedure for a throat swab is direct visualization of the tonsillopharyngeal area and vigorous swabbing of the tonsils or tonsillar crypts and of the posterior pharyngeal wall [115]. The gold standard test for detection of a GAS in the throat is culture on blood agar. The agar medium used must be enriched to support growth as streptococci are fastidious organisms and must also contain blood to allow observation of beta hemolysis. RADTs allow detection of the presence of the group A carbohydrate antigen directly from throat swabs. Unlike the throat culture, which requires overnight or longer to yield a definitive result, RADTs can be completed in a matter of minutes. Non–group A beta-hemolytic streptococci are classified biochemically by species. Certain strains clearly are capable of causing acute pharyngitis when ingested in high rate. Streptococci of serogroup G have been linked to common-source outbreaks of pharyngitis, usually related to a food product. Group C organisms have given rise to common-source epidemics of pharyngitis, usually caused by consumption of unpasteurized dairy products. Antimicrobial therapy is indicated for individuals with symptomatic pharyngitis after the presence of the organism in the throat is confirmed by diagnostic methods. Treatment of GAS pharyngitis is recommended to prevent acute rheumatic fever and suppurative complications, shorten the clinical course and reduce transmission of the infection in family and school units. [116]. There is no definitive evidence that such therapy can prevent acute glomerulonephritis. A number of antibiotics have been shown to be effective in therapy of GAS pharyngitis. These include penicillins, cephalosporins, macrolides, and clindamycin. Penicillin, however, remains the drug of choice because of its proven efficacy, safety, narrow spectrum, and low cost. Amoxicillin often is used in place of oral penicillin V in young children; the efficacy appears equal. Erythromycin is a suitable alternative for patients allergic to penicilin. First-generation cephalosporins also are acceptable for penicillin-allergic patients who do not manifest immediate-type hypersensitivity to beta-lactam antibiotics.

Conclusion

Infections of the pharynx are an extremely common disorder that mostly has a benign course. Usually all cases, the physicians should discriminate a viral infection, which requires only symptomatic management, from a bacterial infection, which requires specific antimicrobial therapy. This issue is important in order the bacterial pharyngitis can be treated appropriately to minimize the risk of suppurative and nonsuppurative complications. On the other hand, unnecessary and potentially deleterious overtreatment of viral infectons with antimicrobial agents. This chapter has outlined the epidemiologic, clinical, and laboratory 206 Mustafa Gul findings of pharyngeal infections. The physicians should also keep in mind the likelihood of rare but serious pharyngeal infections that may be life threatening and that they require special forms of therapy.

References

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Chapter VIII

Malignant Nasopharyngeal Tumors in Children

Marie-Eve Rouge 1, Hervé Brisse 2, Sylvie Helfre 3, Natacha Teissier 4, Paul Freneaux 5 and Daniel Orbachi* 1 Pediatrics department, Institut Curie, Paris, France. 2 Imaging department, Institut Curie, Paris, France. 3 Radiotherapy department, Institut Curie, Paris, France. 4 Head and Neck department, Hôpital Robert Debré - Assistance Publique des Hôpitaux de Paris, Paris, France. 5 Pathology department, Institut Curie, Paris, France.

Abstract

Primary malignant nasopharyngeal tumors are relatively rare in children. The most frequent childhood neoplasms in this region are rhabdomyosarcoma (RMS), Undifferentiated Carcinoma of Nasopharyngeal Type (UCNT) and Non-Hodgkin‘s Lymphoma (NHL). Children with these tumors usually present with nasal obstruction, headache, nasal swelling or cervical node involvement. The nasopharyngeal mass may be discovered during an ear, nose and throat examination and is confirmed by medical imaging. The diagnosis may be suspected on fine needle aspiration and is confirmed by biopsy of the nasopharyngeal mass or cervical lymph node. The treatments and prognoses differ for these 3 types of tumors. The objective of this paper is to review the diagnostic and therapeutic approach to childhood malignant nasopharyngeal tumors such as RMS, NHL and UCNT. The authors also review the known prognostic factors of these diseases in order to discuss treatment adaptation, especially in young children.

* Corresponding author: Département de pédiatrie, Institut Curie, 26, rue d‘Ulm, 75005 Paris, France, Telephone: 0033144324550, Fax: 0033153104005, E-mail: [email protected] 214 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre et al.

Keywords: Nasopharyngeal tumor, children, lymphoma, undifferentiated carcinoma, rhabdomyosarcoma.

1. Introduction

Malignant nasopharyngeal tumors in children essentially consist of Rhabdomyosarcoma (RMS), Undifferentiated Carcinoma of Nasopharyngeal Type (UCNT) and Non-Hodgkin‘s Lymphoma (NHL). More exceptionally, other malignant tumors can involve the nasopharynx; they usually occur in a context of local extension of an adjacent tumor such as a retrostyloid neuroblastoma or, even more rarely, Ewing‘s sarcoma of the facial bones. Certain benign but locally aggressive tumors can also be observed in this region, such as parapharyngeal desmoid fibromatosis, nasopharyngeal angiofibromas derived from the nasal region posterior to the sphenopalatine foramen, chordomas of the clivus, rare craniopharyngiomas extending to the base of the skull and teratomas in neonates.

2. Clinical Presentation

Nasopharyngeal tumours are deeply situated, under the base of the skull, which explains the varied and often late clinical features related to invasion of adjacent structures. Depending on the extent of the tumor, the child may present one or several symptoms at diagnosis, none of which are specific(1), such as headache, hearing loss, nasal obstruction, anosmia, epistaxis, trismus related to invasion of masticatory muscles, disorders of deglutition due, among other things, to invasion of the hypoglossal nerve (XII), dysphonia due to invasion of the vagus nerve (X) or diplopia due to invasion of the abducens nerve (VI). Cervical lymphadenopathy is also a frequent presenting sign (30%). It typically involves the spinal or superior jugulo-carotid chains and may be the presenting sign of malignant lymphoma involving lymphoid formations of Waldeyer‘s ring (2) or a lymphophilic tumor such as UCNT. Nasal obstruction can be infrequently associated with clear cerebrospinal fluid rhinorrhoea suggesting osteo-meningeal invasion, associated with a risk of bacterial meningitis. More rarely, the diagnosis is made in an acute setting with bleeding from the nose and mouth (3) or respiratory distress in cases with very large proliferation obstructing the upper airways. The tumor may sometimes be masked by a benign inflammatory polyp of the nasal fossa.

3. Initial Assessment

The initial clinical work-up of patients with a nasopharyngeal tumor consists of endoscopic rhinoscopy associated with palpation of cervical lymph nodes and meticulous examination of cranial nerves. A mass, sometimes bleeding or inflammatory, may be demonstrated in the nasopharynx, with variable extension to the nasal fossae or oropharynx. Malignant Nasopharyngeal Tumors in Children 215

Clinical examination must systematically look for the presence of cervical lymphadenopathy. Malignant tumors of the nasopharynx only rarely present at the stage of distant metastases. However, hepatosplenomegaly or mediastinal or abdominal lymph nodes may be detected in non-Hodgkin‘s lymphoma, and bone, lung and liver metastases may be observed in rhabdomyosarcomas or UCNT. UCNT may also exceptionally present, especially in the case of lung metastases, with a paraneoplastic syndrome, such as hypertrophic osteoarthropathy (4); the clinical presentation comprises bone pain, synovitis and arthralgia and radiologic signs comprising distal periosteal osteophytosis, predominantly in the upper limbs (5). Imaging constitutes a key element in the diagnostic assessment of nasopharyngeal tumors (6). CT or MRI of the upper aerodigestive tract from the skull to the base of the neck completes the clinical examination. MRI is the imaging technique of choice because it provides the best tissue contrast (7). It can be used for the initial staging assessment, including at the intracranial level, and to evaluate tumor reduction in response to treatment. MRI distinguishes the tumor from adjacent muscles and inflammation of the adjacent nasal sinuses and oropharyngeal mucosa. For a long time, skull base studies could only be performed by CT, but MRI is also efficient and may be more rapidly sensitive than CT, by demonstrating tumor infiltration before the stage of osteolysis. MRI and CT can be combined in image fusion techniques for radiotherapy planning, when indicated. The diagnosis is subsequently confirmed by histologic and immunohistochemical examination of a surgical biopsy sample of the nasopharyngeal tumor or a regional lymph node. Part of the sample, as for all pediatric tumors, is systematically stored in sterile culture medium for cytogenetic analysis and a fragment is frozen to perform molecular biology studies necessary for diagnostic confirmation.

4. Rhabdomyosarcomas

Rhabdomyosarcomas (RMS) are the most common malignant tumor of the facial bones in children (8, 9). All sites combined, they represent 4 to 8% of all childhood malignant tumors and 50 to 60% of all malignant soft tissue tumors.

Epidemiology

Two frequency peaks of RMS are observed regardless of the site: between the ages of 2 and 5 years and at adolescence. The median age at diagnosis of parameningeal RMS is about 5 years (10). The International Society of Pediatric Oncology (SIOP) malignant mesenchymal tumor working party classifies RMS of the head and neck into several groups according to the initial tumor site (11-14):

- Parameningeal RMS (about 50% of head and neck sites), including sites at high risk of meningeal extension, comprising, by definition, nasopharyngeal RMS and tumors derived from or extending to the following structures: base of the skull, paranasal sinus, infratemporal fossa, middle ear or mastoid. 216 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre et al.

- Orbital nonparameningeal RMS (25% about) for tumors with a strictly intraorbital origin. - Other sites (about 25%) in the head and neck situated away from meningeal structures. - Nasopharyngeal RMS represent about 33% of all RMS of the facial bones and neck.

Histopathology

Histologically, this tumor is composed of cells with striated muscle cell differentiation in a population of round or spindle-shaped cells. Immunohistochemistry confirms the muscle differentiation by showing positive labeling for desmin, HHF35, striated muscle actin and possibly myoglobin or Myo D1 (15). The various histologic subtypes of RMS can be observed in the head and neck (16):

- nonalveolar RMS including embryonic RMS with an ―intermediate‖ prognosis, botryoid RMS with a more favourable prognosis often grouped histologically with embryonic RMS and the so-called undetermined and pleiomorphic RMS (10, 16). - alveolar RMS, with a poor prognosis due to their high potential for metastasis and recurrence. In parameningeal sites, the alveolar form represents 18% of cases (10). The alveolar nature of the RMS is subsequently confirmed in 70% of cases by RT- PCR or fluorescence in situ hybridization (FISH) demonstration of a fusion transcript derived from the pathognomonic t(2;13) translocation or its t(1;13) variant or by direct demonstration of the fusion (FISH). These translocations bring the PAX 3 gene, known to regulate transcription of the early phases of neuromuscular development, and the FKHR gene belonging to the transcription factor family, into close contact. Fusion of these 2 genes is probably responsible for activation of the transcription leading to the observed phenotypic modifications (17-20). These translocations can also be identified by classical cytogenetic methods.

Other investigational biological studies (ploidy, hybridization, comparative genomics) are performed in the context of research protocols and their diagnostic or prognostic value have not yet been demonstrated. Staging is currently defined according to the IRS (International Rhabdomyosarcoma Study) classification and is based on postoperative evaluation (Table I), as lesions are systematically biopsied or operated at diagnosis (21). Due to their marked extension at presentation, their site and their classical clinical presentation, most nasopharyngeal RMS are simply biopsied to confirm the diagnosis, corresponding to IRS group III.

Staging Assessment

The initial staging of nasopharyngeal RMS, in addition to physical examination, comprises local assessment (CT or MRI of the head and neck) (Figure 1), a study of the Malignant Nasopharyngeal Tumors in Children 217 neuraxis for tumors with intracranial extension (MRI, cytologic analysis of cerebrospinal fluid) and distant assessment (chest CT, Technetium 99m bone scan, bone marrow biopsy and cytology) (22). MRI is the technique of choice for staging and to evaluate tumor response after neoadjuvant chemotherapy (6, 7). On imaging, RMS have a nonspecific density and tissue signal and are contrast-enhanced. Very large tumors can be necrotic, but tumors are rarely calcified. They present variable radiologic signs of invasion; they can be either circumscribed or invasive, destroying bony structures of the base of the skull and extending intracranially into cavernous sinuses or basal cisternae.

Table I. IRS (International Rhabdomyosarcoma Study) postoperative classification of rhabdomyosarcomas (21).

IRS Group I: Localized disease, completely excised, regional lymph nodes not involved IRS Group II: IRS IIA: Macroscopically resected tumor with microscopic residual disease tumor with a macroscopically complete resection but microscopically incomplete without lymphadenopathy IRS IIB: Regional disease with involved lymph nodes, completely resected with no microscopic residual disease IRS Group III: Macroscopic residual tumor after surgery or diagnostic biopsy IRS Group IV: Distant metastasis at diagnosis (lungs, bone, bone marrow)

Figure 1. Head MRI showing an embryonic rhabdomyosarcoma of the nasopharynx and left nasal fossa, parameningeal, IRS III, less than 5 cm, in a 5-year-old girl presenting with bloody nasal congestion. 218 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre et al.

Treatment

Treatment is usually conducted according to a protocol in the context of European (European Pediatric Soft Tissue Sarcoma Group [EpSSG]) or North American (International Rhabdomyosarcoma Study Group [IRSG]) international prospective studies, stratified according to known prognostic criteria. Treatment is based on neoadjuvant chemotherapy after biopsy, as this site is usually inoperable immediately, followed by a combination of external beam radiotherapy and adjuvant chemotherapy. Neoadjuvant chemotherapy for localized tumors comprises alternating courses of VAC or IVA, containing an alkylating agent (cyclophosphamide [Endoxan®] or ifosfamide [Holoxan®]) together with vincristine [Oncovin®] and actinomycin [Cosmegen®]. Systematic combination with other drugs such as adriamycin [Doxorubicin®], etoposide [VP16®] or carboplatin [Paraplatine®] has not always been demonstrated to be useful in randomized comparative studies of first-line therapy. The combination of doxorubicin and maintenance treatment (vinorelbine and cyclophosphamide) with conventional treatment is currently being tested in localized forms of nasopharyngeal RMS in the context of a European randomized trial (EpSSG). Metastatic tumors are treated by one year of chemotherapy and local treatment. Local control of these frequently extensive tumors is rarely possible by surgery alone, which would be excessively destructive in most cases. However, for small tumors or when the tumor regression after neoadjuvant chemotherapy suggests the possibility of complete resection, surgery, usually microscopically incomplete, can be proposed. Radiotherapy must be administered systematically in this site. It is classically delivered to the initial tumor volume comprising a safety margin, and to the cervical lymph nodes initially involved, taking into account critical organs and dose constraints. In order to protect adjacent cerebral structures, new radiotherapy techniques using intensity modulation, tomotherapy and proton therapy, are particularly adapted for these tumor sites. The total dose delivered is between 41.4 and 50.4 Gy with a boost of up to 54 Gy to inoperable macroscopic residual tumor, in fractions of 1.8 Gy with 5 fractions per week. In order to avoid early progression, especially in the case of associated cranial nerve palsy or intracranial extension, the North American IRSG group recommends radiotherapy at the beginning of treatment concomitantly with chemotherapy, but this modality is often associated with considerable local toxicity (mucositis) (10, 11). In the European EpSSG protocols, radiotherapy is used at the ninth week of treatment (after 3 courses of chemotherapy) (23, 24). Systematic irradiation of the entire base of the skull is no longer recommended. Long-term sequelae are frequent in this site and are related to the child‘s age at the time of radiotherapy, the volume irradiated, the proximity of vital structures, the total dose and the dose per fraction, and the extent of the initial tumor(10). Cure of parameningeal RMS by exclusive chemotherapy, without radiotherapy, initially proposed in children under the age of 3 years in the SIOP group, in an attempt to avoid neurocognitive or esthetic sequelae in young children, is unlikely, as 75% patients not treated by radiotherapy relapse (23). The indication for radiotherapy in this site therefore remains mandatory, regardless of the child‘s age. New techniques, such as tomotherapy, which would improve irradiation fields, appear promising in this site but have not been validated in pediatric populations. Malignant Nasopharyngeal Tumors in Children 219

Prognosis

The main favourable prognostic criteria in RMS are age (less than 10 years), size of the tumor (less than 5 cm), embryonal histologic type, limited initial extension and low IRS stage (21). The 5-year overall survival, regardless of site, is 78%. In contrast, the parameningeal site constitutes an independent unfavourable prognostic factor (24, 25), as survival of localized parameningeal RMS is situated between 64% (5-year survival, SIOP MMT 89 (24)) and 72% (3-year survival, IRS IV (26)). Metastatic forms have a more severe prognosis with a 5-year overall survival between 20% and 50% (27). Similarly, forms with a non-embryonal histology, arising in the maxillary sinus or infratemporal fossa and age at diagnosis more than 10 years constitute forms with a poor prognosis (10, 13).

5. Undifferentiated Carcinoma of Nasopharyngeal Type

In Europe, undifferentiated carcinoma of the nasopharyngeal type is a rare tumor, representing only about 1% of all childhood cancers (28-30), but it nevertheless represents one-third of all malignant tumors of the nasopharynx.

Epidemiology

This tumor mainly affects adolescents and young adults. In pediatric populations, the age of diagnosis is situated between 12 and 15 years (31). The geographical distribution of nasopharyngeal carcinoma represents one of the major characteristics of the disease (32), as this tumor is much more frequent in China and North Africa, suggesting a genetic association (33), an associated viral cause (EBV) (34) or the role of certain dietary habits (excessive salt intake, Vitamin C deficiency) (35). EBV is frequently detected in the genome of tumor cells by immunohistochemistry hybridization using the EBER 1 probe and the copy number is inversely proportional to the degree of histological differentiation. For example, type III UCNT contains a large quantity of viral genome (36).

Histopathology

UCNT is one of the rare pediatric tumors of epithelial origin (carcinoma). The diagnosis, often very strongly suspected on analysis of the cell smear derived from lymph node aspiration cytology, is confirmed by histologic examination after cervical lymphadenectomy or biopsy of the nasopharyngeal mass (37). The most frequent histological type of carcinoma of the nasopharynx in childhood is the undifferentiated form Type III of the WHO classification: > 90% of cases (31, 38, 39). Undifferentiated carcinoma of nasopharyngeal type usually arises in the pharyngeal recess. The presenting sign is usually cervical lymphadenopathy, as the nasopharyngeal 220 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre et al. lesion may remain clinically silent for a long time. At diagnosis, the disease is often locally advanced (58% T3 and 72% N3 in the TNM classification (40)). However, metastases are initially rare (1 case in a series of 34 pediatric patients (31)). When metastases are present, the most frequent metastatic sites are the lungs, mediastinum, bone and liver. Staging is currently based on the 5th AJCC classification (41) (Table II).

Table II. TNM classification of nasopharyngeal carcinomas (41).

T1 Tumor confined to nasopharynx T2 Tumor extends to soft tissues of oropharynx and/or nasal cavity T2a without parapharyngeal extension T2b with parapharyngeal extension T3 Tumor invades bony structures T4 Tumor with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx or orbit N1 Unilateral metastasis in lymph node < 6cm above the supraclavicular fossa N2 Bilateral metastasis in lymph nodes < 6cm above the supraclavicular fossa N3 metastasis in lymph nodes > 6cm and/or in the supraclavicular fossa N3a > 6cm N3b in the supraclavicular fossa M0 No distant metastasis M1 Distant metastasis

Figure 2. Undifferentiated carcinoma of nasopharyngeal type (T4N2BM0) in a 14-year-old boy presenting with headache. Head MRI showing a lesion in the posterior part of the nasal fossae and nasopharynx, with no adjacent bone invasion. Malignant Nasopharyngeal Tumors in Children 221

Staging Assessment

Clinical and radiologic local and regional staging is identical to that of RMS (Figure 2) (42). The presence of metastases is investigated by chest computed tomography, technetium bone scan and, depending on the clinical signs, bone marrow assessment (bone marrow aspiration and biopsy) as well as cytological analysis of cerebrospinal fluid, especially in the case of radiologic signs of invasion of the base of the skull or associated cranial nerve palsy. Positive EBV serology is an indirect marker of EBV infection. The typical serologic profile comprises elevation of IgA directed against the viral capsid antigen (VCA) and high anti-EBNA IgG levels (43). The magnitude of initial serum antibody levels and variations during treatment do not appear to be correlated with prognosis (44, 45). Lactic dehydrogenase appears to be a useful tool for lymph node staging.

Treatment

Surgery has no place in the curative treatment of UCNT apart from biopsy during the initial assessment to obtain adequate histological material for diagnosis. The radiosensitivity of the tumor has been clearly established and local external beam radiotherapy of the nasopharynx and lymph nodes remains the standard treatment of this disease (at doses between 50 and 65 Gy). Radiotherapy is mainly delivered to the nasopharynx (including the base of the skull when initially invaded). Bilateral cervical lymph node chains are also systematically treated with curative intent in the case of initial invasion or preventively when they are not initially invaded. The usual doses are delivered by fractions of 1.8 Gy per session, 5 days a week, but dose reduction allows improved tolerance and decreased sequelae, as radiotherapy can cause salivary gland dysfunction (with hyposialia or asialia), deafness, cervical skin and soft tissue fibrosis, dental dysplasia, pulmonary fibrosis, residual trismus, mandibular hypoplasia or hypothyroidism (31). The use of modern techniques such as intensity modulation radiotherapy (IMRT) or tomotherapy, protects the salivary glands, parotid and cochleas and should decrease the late sequelae in these organs (46, 47). The overall survival and recurrence-free survival (RFS) after exclusive radiotherapy in children are < 40% (48) and sometimes even lower (49). Patients in relapse have a very poor prognosis regardless of the treatment proposed. UCNT is an extremely chemosensitive tumor (31) and neoadjuvant chemotherapy also improves the conditions of radiotherapy by decreasing neck pain and stiffness, thereby facilitating positioning of the child for irradiation. It also improves radiation fields by delineating the irradiation margins between the tumor and adjacent structures (50). Due to the small size of published series, no prospective comparative study has been able to demonstrate a statistically significant survival gain by the addition of neoadjuvant chemotherapy in children. Although the value of chemotherapy on long-term survival has not been formally demonstrated in this tumor by comparative studies, the great majority of pediatric teams recommend a combination of chemotherapy and radiotherapy in the management of children with UCNT either in the neoadjuvant setting, concomitantly and sometimes as adjuvant therapy after radiotherapy (31, 40, 51-53). Recent series reporting the results of chemotherapy and radiotherapy combinations show an improvement of overall 222 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre et al. survival by about 77% (31, 41, 54). Most pediatric protocols therefore combine several drugs, including cisplatin, with a high response rate to chemotherapy exceeding 75% (31). Many teams therefore administer neoadjuvant chemotherapy prior to radiotherapy to obtain better local control, to sterilize any micrometastases and to improve overall survival (55, 56). The other most effective drugs in this disease are doxorubicin, bleomycin, 5-fluorouracil and vinca alkaloids. Some series have reported good results with a 32-month recurrence-free survival (RFS) of 91% in children or adolescents with locally advanced UCNT with treatment comprising neoadjuvant chemotherapy with methotrexate, cisplatin and 5- fluorouracil, local and cervical radiotherapy and adjuvant interferon therapy (57). Due to the major sequelae and good overall prognosis of this disease, current treatment protocols are designed to decrease the total doses of irradiation delivered to the neck and nasopharynx, particularly following a good response to neoadjuvant chemotherapy (31). The role of adjuvant chemotherapy after radiotherapy is more controversial, as contradictory results have been reported in adults (56, 58, 59). A few, non-comparative retrospective,(52, 53, 60) or prospective (51) studies in children have nevertheless shown a possible beneficial effect of this combination, which is limited by the toxicity induced by the chemotherapy-radiotherapy combination.

Prognosis

In the Institut Curie series of 34 children treated for UCNT between 1978 and 2005 by a combination of chemotherapy and radiotherapy, the 5-year overall survival was 73 ± 8% and the recurrence-free survival was 75 ± 8% (31). T stage and N stage at diagnosis, according to the TNM classification, have recently been confirmed to constitute a major prognostic factor (41) (Table II). Pao et al. reported a survival of almost 100% in T1 or T2 patients versus only 35% in children with stage T3-T4(40). Erosion of the skull base and cranial nerve involvement at diagnosis also appear to be unfavorable prognostic factors (61). The presence of distant metastases is associated with a very poor prognosis, with an expected survival of less than 20%.

6. Non-Hodgkin’s Lymphoma of the Nasopharynx

Childhood non-Hodgkin‘s lymphoma (NHL) of the nasopharynx differs from that observed in adults by a more limited histology, frequent extranodal clinical presentation, rapid tumor growth and early dissemination to bone marrow and the central nervous system. The nasopharynx is a possible site of NHL in children and the head and neck represent up to 17% of all primary sites of NHL (3, 62, 63).

Malignant Nasopharyngeal Tumors in Children 223

Epidemiology

The frequency of lymphomas has a variable geographical distribution. In Equatorial Africa, lymphomas represent 50% of all childhood tumors with a majority of Burkitt‘s lymphomas. In Europe, lymphomas represent about 10% of all childhood cancers with an incidence of about one child in 40,000 (64). Non-Hodgkin‘s lymphomas are 1.5 times more frequent than Hodgkin‘s lymphomas. Boys are more often affected by NHL than girls (sex ratio : 2.5 to 3:1). The risk of NHL is increased in children with congenital or acquired immune deficiency.

Histopathology

NHL corresponds to a malignant, clonal proliferation of immature lymphoid precursors that have lost the capacity to differentiate. This proliferation can result from a translocation bringing the c-Myc proto-oncogene, situated on chromosome 8t, in contact with the heavy immunoglobulin chain locus, situated on chromosome 14 (63). This rearrangement induces excessive production of c-Myc inducing continuous cell proliferation (65). The Epstein-Barr virus has been suggested to play a role in malignant transformation, even in immunodeficient children, as this virus can induce a polyclonal B lymphocyte proliferation (66). Cytogenetic studies have shown that Burkitt‘s lymphoma cells usually contain one of the three characteristic translocations t(8;14), t(5;8), or t(8;22) detected by cytogenetic techniques (classical or FISH) after aspiration cytology of the tumor (67). Two settings of nasopharyngeal NHL must be distinguished: NHL in immunocompetent children and NHL, mainly induced by the EBV virus, in immunocompromised children following bone marrow or organ transplantation.

7. NHL in Immunocompetent Children

Histologically, childhood NHL are often diffuse with high-grade malignancy; more than one half of these tumors are Burkitt‘s lymphomas (3). Non-Burkitt‘s lymphoblastic NHL are slightly less frequent. The other rare forms are large cell lymphoma or anaplastic large cell lymphoma.

Diagnosis

The diagnosis is confirmed by immunocytologic analysis after aspiration in the case of Burkitt‘s lymphoma or by immunohistology after biopsy of the nasopharyngeal tumor or a lymph node. Histologic examination of the tumor completed by immunohistochemical studies allow classification of the lymphoma into one of three treatment groups: Mature B, non-B (i.e. T or immature B) or anaplastic large cell. The following tests are also performed:

224 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre et al.

- screening for EBV virus by in situ hybridization (EBER or LMP probe), as EBV is frequently present in Burkitt‘s lymphoma cells; - cytogenetic studies to detect the characteristic translocations and particularly FISH analysis looking for a translocation involving chromosome 8,

Figure 3. Non-Hodgkin‘s lymphoma in a 17-year-old boy presenting with respiratory distress. CT scan of the base of the skull showing a tumor of the parapharyngeal space extending to the retrostyloid space, invading the nasopharynx and infratemporal fossa opposite the foramen ovale. Ipsilateral left cervical lymphadenopathy can also be seen descending as far as the left spinal and retropharyngeal territory (not visible on the Figure).

- molecular biology studies allowing analysis of the clonal characteristics of the proliferation (presence of a monoclonal rearrangement of immunoglobulin or T lymphocyte receptor genes).

Staging Assessment

The initial clinical and radiologic local and regional staging is identical to that of the previous tumors (Figure 3). Distant staging must include the detection of other nodal, hepatic, splenic or abdominal lesions by physical examination. Meningeal involvement is systematically investigated by CSF analysis after lumbar puncture. Chest x-ray or chest CT is also performed looking for an associated mediastinal lesion, and abdominal ultrasound or abdomen and pelvis CT are performed to detect any infradiaphragmatic involvement. An Malignant Nasopharyngeal Tumors in Children 225 associated thoracic or abdominal lesion is detected in 18% of cases (3). Finally, bone marrow invasion is detected by complete blood count looking for cytopenia or abnormal circulating cells and bone marrow aspiration looking for excess blasts. The most widely used classification is the Saint Jude Children‘s Research Hospital or Murphy classification (68)(Table III).

Table III. Murphy’s classification of childhood non-Hodgkin’s lymphoma (Saint Jude Children’s Research Hospital).

Stage I A single tumor or nodal area is involved, excluding the abdomen and mediastinum. Stage II Two or more tumors or nodal areas on one side of the diaphragm, or a primary gastrointestinal tract tumor with or without regional node involvement Stage III Tumors or lymph node areas on both sides of the diaphragm, any primary intrathoracic or extensive intra-abdominal disease. Stage IV Bone marrow (> 25%) or CNS disease regardless of other sites of involvement

Treatment

Surgery is no longer indicated in the treatment of lymphoma, except in the case of biopsy-excision of a very localized tumor and resection of a residual mass during assessment of remission to ensure of the absence of residual cells. Radiotherapy is also not indicated as first-line treatment, despite the radiosensitivity of these tumors. Chemotherapy is therefore the main treatment modality for childhood NHL at the present time. Treatment protocols vary according to the histological type of NHL and staging of the disease. The basic chemotherapy for Burkitt‘s lymphomas or anaplastic large cell lymphomas comprises cyclophosphamide, cytosine arabinoside, vincristine, etoposide, anthracyclines, corticosteroids and neuromeningeal prophylaxis by high-dose methotrexate and administration of intraspinal chemotherapy using methotrexate and cytosine arabinoside. These agents are administered in various combinations as intermittent, short courses for a total duration of about 20 weeks. The treatment of pre-B or T non-Hodgkin‘s lymphoma is similar to that of acute lymphoblastic leukemia with induction and re-induction phases and maintenance treatment for a total duration of about 18 months.

Prognosis

The prognosis of NHL has been considerably improved over the last twenty years. Before 1970, only 5% to 30% of children were cured, while the current cure rate is 70 to 90% depending on the stage (63, 68). The prognosis of these diseases is related to Murphy stage, 226 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre et al. histologic type, response to induction chemotherapy and achievement of remission at the end of treatment.

8. NHL in Immunodepressed Children

The risk of NHL is increased in children with congenital immune deficiency such as ataxia- telangiectasia (Wiscott-Aldrich syndrome), or acquired immune deficiency due to Human Immunodeficiency Virus (HIV) or EBV infection or after organ or bone marrow transplantation (69, 70). Post-transplant lymphoproliferative disorders (PTLD) constitute a serious complication of transplantation with a mortality of up to 90% [Leblond, 1995 #83]. In 80% of cases, PTLD are related to EBV-induced proliferation of B lymphocytes (71). EBV is a virus belonging to the herpes viridae family. Epithelial cells of the oropharynx constitute the primary site of infection, leading to infection of B lymphocytes during their passage in pharyngeal lymphoepithelial tissues. In immunocompetent subjects, infected B lymphocytes are activated, resulting in a polyclonal proliferation. This proliferation is controlled and the virus remains latent in the body where it establishes an equilibrium: specific T lymphocyte cell-mediated immunity destroys infected B lymphocytes (72). Disruption of this equilibrium can be due to the use of immunosuppressives following organ or bone marrow transplantation. A cellular event (8-14 translocation involving the c-myc oncogene but also alteration of repair proteins such as p53) can also occur, explaining the delayed onset of PTLD when the immune deficiency is less severe, independently of the presence or absence of EBV. In the first situation, treatment consists of decreasing immunosuppression and, in the second situation, more conventional chemotherapy appears to be justified.

Diagnosis

In the post-transplant setting, the presenting signs of PTLD of the nasopharynx may be snoring, nasal speech or upper airway dyspnea. Nasopharyngeal lymphomas constitute a heterogeneous group of malignant proliferations and their frequency in children justifies a specific ENT examination in the presence of any atypical clinical features, especially in a context of immunosuppression. The prognosis depends on early diagnosis due to the rapid progression of these lymphomas in children. PTLD can have a polymorphic clinical presentation. They have similar features after organ or bone marrow transplantation, but with different times to onset: median of 9 months after organ transplantation and 3 months after hematopoietic stem cell transplantation (HSCT). This difference is due to the longer duration of immunosuppression after solid organ transplantation. The first sign of PTLD may be moderate mononucleosis associated with fever. Patients can present localized lymphadenopathies or disseminated disease involving the gastrointestinal tract, liver, kidneys, central nervous system or bone marrow; 50% of PTLD are confined to lymph nodes (3) Malignant Nasopharyngeal Tumors in Children 227

In this setting, the diagnosis is based on histologic examination of a biopsy of the mass. The presence of clinical and laboratory signs of mononucleosis and a very high EBV viral load associated with a nasopharyngeal mass may be sufficient to establish the diagnosis in the absence of mass accessible to biopsy in PTLD after bone marrow transplantation. Due to its often dormant or rapidly invasive course, 15% in 50% of cases of PTLD are diagnosed at autopsy. Patients presenting symptoms suggestive of PTLD must undergo identical staging to that of immunocompetent children with NHL. The laboratory work-up must comprise EBV viral load, immunoelectrophoresis to detect a monoclonal immunoglobulin peak and B-cell lymphocytosis.

Treatment

Immunosuppressive therapy must be systematically decreased as far as possible, which achieves remission of PTLD in 25% of cases (71). Reduction of immunosuppressive therapy is sometimes impossible in the case of vital organ transplants (heart, liver). Conventional chemotherapy is therefore reserved to these situations and late-onset monoclonal PTLD. Response rates to chemotherapy in this setting range from 33% to 100% (71). Other cell therapy or anti-B antibody approaches can be associated with reduction of immunosuppression. A clinical trial conducted with a murine human chimeric anti-B antibody (anti-CD20 Ab) (73) showed a response rate of 66% with good safety and complete remission after a median of 25 days after the first dose. The anti-CD20 antibody, rituximab, is a chimeric monoclonal antibody that has been used in low-grade relapsing non-Hodgkin‘s lymphoma and PTLD, sometimes with a good response to treatment (74, 75). However, toxicity can include respiratory distress and shock probably related to tumor lysis syndrome(76). EBV antiviral therapy has a limited effective. Anti-EBV cell therapy is currently under evaluation (77, 78). Future treatments will probably be based on the use of monoclonal antibodies in post-transplant lymphoproliferative disorders and NHL in immunocompetent children, allowing simplification of current chemotherapy protocols. When feasible, surgery can confirm the diagnosis while sometimes reducing the tumor mass and can be effective in isolated gastrointestinal lesions. However, it must be associated with reduction of immunosuppression to avoid recurrence of the lymphoproliferative disorder. Radiotherapy, although rarely used, may sometimes be indicated, mainly in PTLD of the central nervous system.

Prognosis

The overall prognosis of PTLD is difficult to assess. About 25% of cases regress after decreasing immunosuppressive therapy in the context of an organ transplant. The regression rate is lower after bone marrow transplantation due to persistence of an immune deficiency despite discontinuation of immunosuppression. Chemotherapy may be justified in the 228 Marie-Eve Rouge, Hervé Brisse, Sylvie Helfre et al. absence of tumor regression, but these lymphomas are often chemoresistant, with a poor prognosis due to the increased toxicity of these treatments in these settings (79). Early-onset PTLD appear to have a better prognosis than late lesions. The early mortality rate for patients requiring chemotherapy is very high, ranging from 64% to 91% (71). Isolated lesions appear to have a better prognosis than multifocal PTLD. Central nervous system lesions are associated with a very poor prognosis with a mortality of up to 82%

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Chapter IX

Harmonic Scalpel® in the Treatment of Snoring

A. Salami, R. Mora, M. Bavazzano, L. Guastini, B. Crippa and M. Dellepiane ENT Department, University of Genoa, Italy.

Abstract

Primary snoring is usually considered to be a consequence of soft palate vibration caused by a partial upper airway collapse during sleep. Uvulopalatopharyngoplasty (UPPP) is a surgical treatment used to remove tissue in the throat for snoring and/or sleep apnea syndrome. UPPP is still the most frequently used surgical treatment for snoring and/or sleep apnea syndrome. Innovative advances have recently introduced regarding instrumentation, energy sources, and devices aimed at facilitating surgical procedures in terms of efficient hemostasis, tissue legation and dissection, as well as reduction in surgical time: although curative for many patients, these procedures present side effects. The Ultracision Harmonic Scalpel® is an ultrasonic cutting and coagulating surgical device. The equipment consists of a generator, an hand-piece, and specific inserts. The mechanism of the Harmonic Scalpel® (HS) is based on transforming electrical energy into mechanical movement of 55.5 kHz frequency. The high-frequency ultrasonic vibrations produced by the HS cause an effect referred to as cavitation whereby the collagen and proteoglycans in the tissue become denatured and then combine with the tissue fluids to form a coagulum. The pressure exerted on the tissue by the blade surface collapses blood vessels and allows the coagulum to form a hemostatic seal. The HS controls bleeding by coaptive coagulation at low temperatures, ranging from 50°C to 100°C. By contrast, electrosurgery and laser coagulate by burning (obliterative coagulation) at higher temperatures (150–400°C). The vibration frequency of HS is optimal for soft tissue and does not cut mineralized tissue (lower frequency waves need to be utilized). In UPPP, among the available hand-pieces and inserts, a specific hand-piece and insert was preferred: the insert, shaped like scissor, had a sharp inner beveled radius for 236 A. Salami, R. Mora, M. Bavazzano et al.

cutting under tension, a blunt outer radius for coaptive coagulation, and a flat side for surface coagulation. In all the patients treated, the HS allowed rapid and easy intraoperative management and a precise and safe cut, especially in difficult anatomic sites. The operating fields were blood free with perfect intraoperative visibility. These features facilitate the use of the HS in tight spaces, where precision is essential. Postoperatively, all patients had a recovery of snoring (no complications with regard to haemostasis or other major complication, were noted in our study group), with an acceptable level of pain.

Introduction

Snoring is the vibration of respiratory structures and the resulting sound, due to obstructed air movement during breathing, while sleeping. In some cases the sound may be soft, but in other cases, it can be rather loud and quite unpleasant. The respiratory structures are usually the uvula and soft palate (velum). Snoring affects around 25% of adults and Obstructive Sleep Apnea Syndrome (OSAS) approximately 4% of adults [1]: almost half of adults snore at least occasionally. Snoring occurs when air flows past relaxed tissues in the throat, causing the tissues to vibrate as the patient breathes, creating hoarse or harsh sounds. Snoring is a result of incomplete pharyngeal obstruction. Turbulent airflow and subsequent progressive vibratory trauma to the soft tissues of the upper airway are important factors that contribute to the condition. Anatomic obstruction leads to increased negative inspiratory pressure, which propagates further airway collapse, turbulence, and noise. The imbalance between the forces that act to maintain airway patency (the force of the pharyngeal muscles) and the negative inspiratory forces generated by the diaphragm is thought to be the primary etiology of anatomic obstruction in OSAS. In OSAS, the tongue contacts the soft palate and posterior pharyngeal wall in the presence of lateral collapse of the pharynx, generating occlusion. Significant factors that contribute to this condition include obesity, redundant tissue in the neck, retrognathia, and craniofacial anomalies. In addition, anatomic abnormalities of the nasal airway (eg, septal deviation, inferior turbinate hypertrophy, nasal-valve narrowing, adenoid hypertrophy) may play a role. Alcohol and other sedatives may increase the severity of OSAS. Data from a recent meta-analysis also suggested a causal relationship between OSAS and head and neck cancer (which may first manifest as OSAS) [1].

Pathophysiology of Snoring

Three factors are involved in the development of snoring:

- decreased dilating forces of the pharyngeal dilators, - upper-airway anatomic abnormalities, - negative inspiratory pressure of the diaphragm.

Harmonic Scalpel® in the Treatment of Snoring 237

The site of obstruction is primarily in the pharynx; however, many anatomic sites clearly contribute. The muscles of the upper airway, including the sternohyoid, genioglossus, and tensor palatine, work together to dilate or stiffen the extrathoracic airway and to maintain its airway calibre. Collapse may begin when the base of the tongue abuts the posterior pharyngeal wall and soft palate. This may progress to the lower pharynx. The exact cause of upper airway collapse in humans has not been completely elucidated. An animal study, however, revealed nearly abolished genioglossal activity during rapid eye movement (REM) sleep, even in the presence of elevated inspired carbon dioxide levels. Extended or excessive tissue of the soft palate, a large tongue base, a large uvula, large tonsils, and redundant pharyngeal mucosa are correlated with a narrowed upper airway. With airway narrowing, increased inspiratory pressure is needed to maintain adequate ventilation. A virtual vacuum on inspiration promotes further collapse of the soft tissue, which often has poor tone due to repeated vibratory trauma. Of importance is the finding that increased pulmonary resistance also requires increased negative inspiratory pressures. Nocturnal oxygen desaturation and hypercapnia associated with OSAS increase arterial blood pressure in both the systemic and pulmonary circulations. Over time, hypertension can lead to cardiac hypertrophy and decompensation. ―Core pulmonary” is a classic clinical manifestation of long-standing OSAS. Recent studies provide the evidence that patients with sleep-disordered breathing have a significantly greater risk of developing hypertension and requiring antihypertensive medications [2]. Arrhythmias can also occur as a result of cardiopulmonary strain secondary to hypoxia. In rare cases, this may lead to nocturnal death. Diminished oxygen saturation also stimulates erythropoiesis and clinical polycythemia. Additionally, OSAS has been implicated as a risk factor for first stroke, recurrent stroke, and post stroke mortality [3]. The excessive negative intrathoracic pressures required to overcome obstruction result in morbidity and mortality from cardiac arrhythmias, systemic and pulmonary hypertension and myocardial infarction [4]. The associated sleep fragmentation is thought to be the cause of the resulting chronic daily headache, daytime fatigue, cognitive impairment and increased risk of road tragic accidents [5]. These sequels increase when the number of apnoeas and hypopnoea per hour increase (apnoea-hypopnoea index, AHI), particularly when the AHI is above 20 [6].

Treatment of Snoring

The ‗gold standard‘ treatment for OSAS is tracheotomy as it bypasses the obstruction, but results in undesirable lifestyle and social changes which most patients find unacceptable. An effective alternative is nasal continuous positive airway pressure (CPAP) [7]. Unfortunately, compliance with CPAP is poor with some patients finding it totally intolerable [8]. Several reports highlight the role of surgery in the treatment of snoring. Socially disruptive snoring generally originates in the area of the soft palate and uvula. The validity of this practical observation is supported by reports indicating that surgical procedures directed 238 A. Salami, R. Mora, M. Bavazzano et al. at the soft palate and uvula—primarily, laser-assisted uvulopalatoplasty (LAUP) and uvulopalatopharyngoplasty (UPPP) cure or substantially diminish severe snoring in most patients. Unfortunately, all of these procedures are associated with severe patient discomfort and treatment-related morbidity [9,10]. The morbidity of procedures performed in the region of oropharynx is significant in the early postoperative period: the laser techniques widen the retropalatal space, and subsequent healing leads to reinforcement of the free edge of palate; although the effectiveness of these methods are high, the postoperative period is often associated with pain, dysphagia, and odynophagia [1,11,12]. Early pain and difficulties in swallowing are partially caused by the pharyngeal component of the surgery, at least partially caused by damage to the anterior arches. The extent of the discomfort depends on the depth of damage in the soft tissue. The more sensitive nerve endings are harmed the greater is the odynophagia [1,11,12]. Classic power laser-assisted performances are accompanied with postoperative pain: although the new lasers, as ErCrYSGG present a lower postoperative pain, compared with other laser, the American Medical Association does not approve of the use of lasers to perform operations on the pharynx or uvula [13]. Uvulopalatopharyngoplasty (UPPP) attempts to widen the airway by removing tissues in the back of the throat, including the uvula and pharynx: however, this technique is quite invasive, with risks of side effects. The most dangerous risk is that enough scar tissue could form within the throat as a result of the incisions to make the airway more narrow than it was prior to surgery, diminishing the airspace in the velopharynx. Scarring is an individual trait, so it is difficult for a surgeon to predict how much a person might be predisposed to scarring. Some patients have reported the development of severe sleep apnea as a result of damage to their airway caused by pharyngeal surgery [14]. Despite the variety of treatment options available, the literature suggests that 10 to 40% of patients treated for snoring report unsatisfactory results. The persistence of snoring may be attributable to a misidentification of the sound-generation site or insufficient tissue reduction, but available research has not allowed us to achieve an accurate and comprehensive understanding of the issues associated with treatment failure in these patients [15,16]. Brietzke and Mair suggest that patient selection may play a role in determining the success or failure of treatment. Patient selection might be a worthwhile variable to investigate in any studies of the volumetric tissue-reduction procedure [17]. Radiofrequency ablation is a relatively new surgical treatment for snoring. This treatment applies radiofrequency energy and heat (between 77°C to 85°C) to the soft tissue at the back of the throat, such as the soft palate and uvula, causing scarring of the tissue beneath the skin. After healing, this results in stiffening of the treated area. The procedure takes less than one hour, is usually performed on an outpatient basis, and usually requires several treatment sessions. Discomfort and pain is usually minimal. Radiofrequency ablation is frequently effective in reducing the severity of snoring, but, often does not completely eliminate snoring. The use of radiofrequency energy for volumetric soft tissue reduction of the palate was first described by Powell et al: Powell‘s uvulopalatal flap (UPF) is characterized by its substantial suturing of the uvula to the anterior wall of the soft palate; the uvula is folded Harmonic Scalpel® in the Treatment of Snoring 239 upwards through 180°. The procedure engenders no risk of velum insufficiency, but is very difficult to perform [18]. Same authors have recently proposed less invasive techniques that are easier to implement, such as the UPF and volumetric radio-frequency reduction, both at the nasal and oropharyngeal and hypopharyngeal levels: energy generated via a mono- or bipolar electrode needle causes ablation and coagulation of the soft tissue, followed by fibrosis and shrinkage of the soft palate; this reduction of soft tissue volume can reduce snoring [18-20]. Post- surgical complications are uncommon, though this aspect has not been fully investigated by many authors, through detailed questionnaires. The most frequent complications (1-11% according to the case records) are: nasal regurgitation and rhinolalia caused by velum insufficiency, pharyngeal dryness, bleeding, pharyngeal edema, infections, dehiscence, and altered taste [21-23]. To overcome the limits of the traditional tools, for the first time the ENT Department of the University of Genoa (Chairman Prof. Angelo Salami) - Italy, have introduced the application of the Ultracision Harmonic Scalpel in UPPP.

Harmonic Scalpel®

Innovative advances have recently occurred regarding instrumentations, energy sources, and devices aimed at facilitating surgical procedures in terms of efficient hemostasis, dissection, safety, and reduction in surgical time. The introduction of new operative techniques based on modern technology improve several negative consequences of surgery. UPPP is a surgical treatment used to remove tissue in the throat for snoring and/or sleep apnea syndrome. UPPP is still the most frequently used surgical treatment for snoring and/or sleep apnea syndrome [24]. In the present chapter, we introduce to the practice of ―snoring surgery‖ a new ultrasound instrument: the Ultracision Harmonic Scalpel (Ethicon Endo-Surgery, Cincinnati, USA). Ultrasonic cutting of soft and hard tissues is not an original idea. In our department, the harmonic scalpel (HS) has been used successfully in head and neck surgery (pharyngolaryngectomy, total laryngectomy, partial laryngectomy, thyroidectomy, radical and conservative neck dissections, superficial and total parotidectomy, tonsillectomy, nasal inferior turbinotomy) [25,26]. The HS is an ultrasonic cutting and coagulating surgical device. The equipment consists of a generator, an hand-piece, and specific inserts. The mechanism of the Harmonic Scalpel is based on transforming electrical energy into mechanical movement of 55.5 kHz frequency; vibrating 55,500 times per second, the Harmonic Scalpel blade denatures protein in the tissue to form a sticky coagulum. Pressure exerted on tissue with the blade surface collapses blood vessels and allows the coagulum to form a hemostatic seal. The HS controls bleeding by coaptive coagulation at low temperatures, about 50 °C. By contrast, electrosurgery and laser coagulate by burning (obliterative coagulation) at higher temperatures (150° to 400 °C) [27]. The objective of the present study has been to report our experience with the HS in UPPP. 240 A. Salami, R. Mora, M. Bavazzano et al.

Personal Experiences

The first step was to verify the efficacy and applicability of the hand-piece and the inserts used in the other surgical techniques: the results highlighted the adequacy of the hand-piece and the inserts. Among the available hand-pieces and inserts, specific hand-piece and inserts were preferred: the inserts, shaped like an hook or a scissor, had a sharp inner beveled radius for cutting under tension, a blunt outer radius for coaptive coagulation, and a flat side for surface coagulation. (Figure 1) Pre-operative evaluation consisted of polysomnographic testing, fiberoptic examination, with Müller‘s manoeuvre at the velopharyngeal level and at the retro-basilingual level, and the Friedman staging system to asses patient selection criteria based on Friedman tongue position (FTP), tonsil size, body mass index (BMI) [28]. Before and six months after the treatment, each patient studied was evaluated using:1) apnea-hypopnea index (AHI) [29]; 2) snore levels, recorded from the bed partners on a 10 cm visual analog scale (VAS) from 0 (no snoring) to 10 (extremely disruptive snoring); 3) a standard 10 cm VAS ranging from 0 (no pain) to 10 (intolerable pain) was used to assess postoperative pain on postoperative days 1, and 10. The indication for UPPP was made when prolonged (>1,5 cm) or hypertrophic uvula, redundant mucosa in the soft palate (distance from the posterior edge of the hard palate to the inferior edge of the hard palate > 4 cm), or AHI >15 were noticed [29]. The patients signed informed consent forms and the operations were carried out, under general anaesthesia, with orotracheal intubation and a Boyle-Davis mouth gag within the oral cavity; 20 patients (11 males and 9 females), FTP grade I, tonsil size 2-3 [28], BMI<40 (kg/m2) aged between 28 and 68 years (mean age 49 years) underwent surgery. HS was used in all the surgical step. The generator, that can be adjusted from a level of 1 to 5 to increase cutting speed and decrease coagulation by increasing the blade‘s lateral excursion, was used at level 2 and the activation time didn‘t exceed 10 seconds. Two incisions, each of the same length, were made on each side of the lateral margin of the uvula, at the level of the posterior edge of the soft palate, with upward direction into the soft palate, to retract the tissue and diminish the thickness of the soft palate, according to the characteristics of the soft palate. (Figure 2)

Figure 1. The specific insert used. Harmonic Scalpel® in the Treatment of Snoring 241

Figure 2. The incision made on each side of the lateral margin of the uvula, at the level of the posterior edge of the soft palate, with upward direction into the soft palate (the arrow highlights the cutting line).

After, an excision of the redundant mucosal of each posterior arch and subsequent creation of neouvula by a partial uvulectomy was done. (Figure 3)

Figure 3. Excision of the redundant mucosa of the right posterior arch (the arrow highlights the cutting line). 242 A. Salami, R. Mora, M. Bavazzano et al.

Table 1. Patient data, before (t=1) and 6 months (t=2) after surgery. M: male; F: female; AHI: apnea-hypopnea index; SL: snore levels; pain: post-operative pain at one (A) and 10 (B) days.

No Sex Age AHI SL pain t=1 t=2 t=1 t=2 A B 1 F 41 22 9 8 2 3 1 2 M 46 21 10 8 2 3 1 3 F 68 24 10 9 3 2 0 4 M 48 23 9 8 2 3 1 5 F 45 18 8 7 1 2 0 6 M 37 21 10 8 2 2 1 7 M 59 25 8 9 2 3 1 8 M 61 19 9 7 1 3 0 9 F 45 26 8 8 2 2 1 10 F 58 23 9 8 1 3 1 11 M 49 21 9 7 1 3 0 12 M 68 19 8 7 1 2 1 13 M 49 25 10 8 2 3 1 14 F 54 18 8 7 1 3 0 15 F 35 24 9 8 1 3 0 16 M 45 26 9 9 2 2 1 17 F 28 17 8 7 1 3 1 18 F 46 23 9 8 1 3 1 19 M 56 24 8 9 2 2 0 20 M 39 20 10 8 1 3 1

All the patients underwent tonsillectomy with the HS. In all the patients treated, the HS allowed rapid and easy intraoperative management and a precise and safe cut, especially in difficult anatomic sites. The operating fields were blood free with perfect intraoperative visibility. These features facilitate the use of the HS in tight spaces, where precision is essential. Postoperatively, all patients had a recovery of snoring (no complications with regard to haemostasis or other major complication, were noted in our study group), with an acceptable level of pain. (Table 1)

Discussion

The problem of snoring and OSAS has gained increased awareness in the media and general population during recent years: the prevalence of occasional snoring varies from 29 to 71% and of habitual snoring from 9 to 26%; the more severe disease of OSAS has a prevalence of up to 4% for men and 2% for women, resulting in significant morbility and mortality; morbility results primary from cardiovascular disease, quality of life and performance deficits caused by loss of alertness and daytime somnolence [30,31]. Harmonic Scalpel® in the Treatment of Snoring 243

OSAS is characterized by prolonged, generally partial, upper airway obstruction associated with hypoxemia, hypercapnia and the classic symptoms are snoring, apnea and open mouth: the most common causes are nasal obstruction, adenotonsillar hypertrophy, tongue collapse, cleft palate, craniofacial disorders and genetic mechanism [32]. The mechanisms of OSAS are well established. Pharyngeal muscle relaxation during sleep leads to collapse of the upper airway: the turbinates, palate and tongue base are the most common sites of obstruction. The controversy on indications and contraindications for the standard uvulopalatopharyngoplasty, laser-assisted uvulopalatoplasty and the use of radiofrequency is still ongoing. In surgery, innovative devices have been recently introduced to facilitate surgical procedures in terms of efficient hemostasis, dissection, safety, and reduction in surgical time. The steel blade and monopolar electrocautery have been and remain the mainstay in surgical dissection instruments for the majority of practicing otolaryngologists [25,26,33]: these two instruments are often preferred, although newer, emerging technologies have been demonstrated to improve surgical time, decrease postoperative pain, and reduce collateral tissue damage and unwanted side effect for selected procedures. The HS was originally developed for its application in laporoscopic abdominal surgery but has found its way successfully into the speciality of otolaryngology [25,26]: after the first application in tonsillectomy and thyroidectomy [34], the use of the HS has been described in several surgical techniques in head and neck surgery [25,26]. Our experience shows that the HS reduces the operation time as previously reported for others surgical techniques [25,26]. We believe these results arise from the ability of the HS to simultaneously cut tissue and coagulate, allowing an optimal view in a bloodless operative field. The blood loss is significantly diminished during the dissection as a result of the shortened operation time and the more precise hemostasis. These features facilitate the use of the HS in tight spaces, where precision is essential. The handling of the ultrasonic scalpel does not require special skills from the surgeon, since it only substitutes the conventional electronic scalpel. In all the surgical steps, the HS showed its safety in the cutting and clotting of soft tissue. It did not produce thermal lesions in the neighbour structures, allowing us to work near delicate structures. The cutting speed and extent of coagulation are easily controlled by using power adjustments, the blade edge, tissue tension, and grip force and pressure. Unlike heat-producing devices, the HS uses ultrasonic technology to denature protein by mechanically breaking the hydrogen bonds in protein molecules, thus generating much less heat from tissue friction, which minimizes lateral thermal injury [35]. The lower level of thermal energy transferred to the tissues, which allows the water present within the tissues to persist and not boil, results in a better healing process [25,26,34,35]. (Figure 4) The better healing process justifies the postoperative result observed in the patients treated: no postoperative complications, lower level of pain. (Table 1) The HS has advantages over diathermy in that it does not require a grounded electrode pad, reduces the thermal effects on surrounding tissues, obviates problems associated with electric current leakage, and produces faster re-epithelialization and greater tensile strength 244 A. Salami, R. Mora, M. Bavazzano et al. than laser or electrosurgical instruments [36]. These characteristics justify an important advantage of the HS, i.e. the lower postoperative pain; we believe that it should be mainly attributed to:

Figure 4. Postoperative results after six months.

(1) the sealing properties, (2) the limited thermal spread and injury to the adjacent tissues of HS devices, (3) the better healing process of the tissues treated.

The poorer visualization, due to intraoperative bleeding, and the risk for the surgeon to get out of the proper plane justifies the higher postoperative pain observed in the laser techniques.

The vibration frequency of HS is optimal for soft tissue and doesn’t cut the mineralized tissue (lower frequency waves need to be utilized) [25,26]. Ultrasonic devices able to cut mineralized tissues, use a frequency of 24.5-29 kHz (vibrating 24,500 – 29,000 times per second), and are ineffective on soft tissues [37]. Therefore the HS is not able to cut the bone, moreover its accidental contact with bony structures determines the inactivation of the apparatus [33]. Termal spread from HS is limited to an area less than 1.2 mm beyond the tissue bundle or vessel, respectively on the other hand, high-power ultrasonic dissection may results in considerable heat production and collateral tissue damage, especially when the activation time exceeds 10 seconds, in these cases studies on animals (rabbit) have shown a lasting fibroblastic reaction and a delayed healing process on the other hand, high-power ultrasonic dissection may results in considerable heat production and collateral tissue damage, especially when the activation time exceeds 10 seconds, in these cases studies on animals (rabbit) have shown a lasting fibroblastic reaction and a delayed healing process [38,39]. A lower activation avoids rare complications caused by overheating of the device [40]: for these reasons the generator was used at level 2 and the activation time didn‘t exceed 10 seconds. Harmonic Scalpel® in the Treatment of Snoring 245

The pharyngeal stage of swallowing presumably begins with the triggering of the swallow reflex at the base of the anterior faucial pillars with appears to be the most sensitive place for the elicitation of this reflex [41]. Resection of the anterior faucial pillars is included in various UPPP techniques [14]: the swallow reflex may not be triggered if there is a lack of proprioceptive or cutaneous receptors in this area, with a consequent choking and nasal regurgitation. In our surgical technique, the excision of the redundant mucosa is made at the level of each posterior arch: for this reason and for the HS‘s characteristics no patients of the group A experienced problems of swallowing difficulty.

Conclusions

Sleep medicine is a relatively young clinical discipline. It is therefore hardly surprising that, even after the boom of the 1980s and early 1990s, there continue to be numerous new developments. The increasing drive to cut costs in the healthcare system will promote formations of a consensus on which methods constitute the bare minimum of required diagnostics. Surgical procedures have in general been overshadowed by the development of new technical options: these are resulted by combination of previously known methods and optimized methods of patients selection. The literature reports new trends in the treatment of snoring and/or obstructive sleep apnea. Our data highlight as the HS is a reliable and safe device in UPPP, providing sufficient hemostasis and cutting precision, reducing operation time and the postoperative pain. For these reasons, the HS should be considered a new suitable device in UPPP. The results of this study suggest that HS‘s UPPP results in prolonged subjective and objective improvements: the prolonged symptomatic improvement support the long term effectiveness of HS treatment in subjects with OSAS, specifically with respect to quality of life, symptoms, vigilance and respiratory parameters. But there are some limitations to this study: the possibility that the others participants had worse outcomes than those who had participated; the use of home sleep studies rather than full in-laboratory studies (several data are based on subjective snoring scores evaluated by patients and their bed partners), unfortunately, standardized equipment to measure and objectify snoring noise is not yet available; the variation of snoring from one night to another and sleep quality is different from home in the hospital or a sleep laboratory; therefore, to evaluate snoring, one has to rely on snoring scores of patients and their bed partners. Nevertheless, satisfaction of the patients and bed partners is the aim of surgical treatment for snoring and therefore can be regarded as the criterion of success. However our experience highlights the absence of post-operative complications: no patients treated with HS showed bleeding, rhinolalia, necrosis or other significant side effects; moreover, the operation was rapid and easy to perform, with a lower postoperative pain. In conclusion, HS is a riliable and safe device in UPPP providing sufficient hemostasis, reduced operative time, good postoperative recovery, with lower pain and shorter postoperative stay.

246 A. Salami, R. Mora, M. Bavazzano et al.

References

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[17] Brieczke, S. E. & Mair, E. A. (2003). Injection snoreplasty: Extended follow-up and new objective data. Otolaryngol Head NeckSurg, 128, 605-15. [18] Woodson, B. T., Nelson, L., Mickelson, S., Huntley, T. & Sher, A. (2001). A multi- institutional study of radiofrequency volumetric tissue reduction for OSAS. Otolaryngology Head and Neck Surgery, 125, 303-3112. [19] Boudewyns, A. & Van De Heyning, P. (2000). Temperature- controlled radiofrequency tissue volume reduction of the soft palate (somnoplasty) in the treatment of habitual snoring: results of a European multicenter trial. Acta Otolaryngol, 120, 981-985. [20] Taliaferro, C. (2001). Submucosal radiosurgical uvulopalatoplasty for the treatment of snoring: is the monitoring of tissue impedance and temperature necessary? Otolaryngol Head Neck Surg, 124, 46-50. [21] Croft, C. B. & Golding-Wood, D. G. (1990). Users and complications of uvulopalatopharyngoplasty. J Laryngol Otol, 104, 871-875. [22] Fairbanks, D. N. F. (1990). Uvpp: complications and avoidance strategies. Otolaryngol Head Neck Surg, 102, 239-245. [23] Grontved, A. M. & Karup, P. (2000). Complaints and satisfaction after uvulopalatopharyngoplasty. Acta Otolaryngol Suppl, 543, 190-192. [24] Van den Broek, E., Richard, W., van Tinteren, H. & De Vries, N. (2008). UPPP combined with radiofrequency thermotherapy of the tongue base for the treatment of obstructive sleep apnea syndrome. Eur Arch Otorhinolaryngol, 265, 1361-65. [25] Salami, A., Bavazzano, M., Mora, R. & Dellepiane, M. (2008). Harmonic scalpel in pharyngolaryngectomy with radical neck dissection. J Otolaryngol Head Neck Surg, 37, 633-7. [26] Salami, A., Dellepiane, M., Bavazzano, M., Crippa, B., Mora, F. & Mora, R. (2008). New trends in head & neck surgery: a prospective evaluation of the harmonic scalpel®. Medical Science Monitor, 14, PI1-5. [27] Torkian, B. A., Guo, S., Jahng, A. W., Liaw, L. H., Chen, Z. & Wong, B. J. (2006). Noninvasive measurement of ablation crater size and thermal injury after CO2 laser in the vocal cord with optical coherence tomography. Otolaryngol Head Neck Surg, 134, 86-91. [28] Friedman, M., Ibrahim, H. & Bass, L. (2002). Clinical staging for sleep-disordered breathing. Otolaryngol Head Neck Surg, 127, 13-21. [29] Friedman, M., Vidyasagar, R., Bliznikas, D. & Joseph, N. J. (2006). Patients selection and efficacy of pillar implant technique for treatment of snoring and obstructive sleep apnea/hypopnea syndrome. Otolaryngol Head Neck Surg, 134, 187-196. [30] Hofmann, T., Schwantzer, G., Reckenzaun, E., Koch, H. & Wolf, G. (2006). Radiofrequency tisssue volume reduction of the soft palate and UPP in the treatment of snoring. Eur Arch Otorhinolaryngol, 263, 164-170. [31] Steward, D. L., Weaver, E. M. & Woodson, B. T. (2005). Multilevel temperature- controlled radiofrequency for obstructive sleep apnea: extended follow-up. Otolaryngol Head Neck Surg, 132, 630-635. [32] Mora, R., Salami, A., Passali, F. M., Mora, F., Cordone, M. P., Ottoboni, S. & Barbieri, M. (2003). Int J Pediatric Otorhinolaryngol, 67S1, S229-S231. 248 A. Salami, R. Mora, M. Bavazzano et al.

[33] Carroll, T., Ladner, K. & Meyers, A. D. (2005). Alternative surgical dissection techniques. Otolaryngol Clin N Am, 38, 397-411. [34] Siperstein, A. E., Berber, E. & Morkoyun, E. (2002). The use of the harmonic scalpel vs. conventional knot tying for vessel ligation in thyroid surgery. Arch Surg, 137, 137-42. [35] Lachanas, V. A., Hajiioannou, J. K., Karatzias, G. T., Filios, D., Koutsias, S. & Mourgelas, C. (2007). Comparison of Ligature vessel sealing system, harmonic scalpel, and cold knife tonsillectomy. Otolaryngol Head Neck Surg, 137, 385-9. [36] Sinha, U. K. & Gallagher, L. A. (2003). Effects of steel scalpel, ultrasonic scalpel, CO2 laser, and monopolar and bipolar electrosurgery on wound healing in guinea pig oral mucosa. Laryngoscope, 11, 228-36. [37] Salami, A., Verecellotti, T., Mora, R. & Dellepiane, M. (2007). Piezoelectric bone surgery in otologic surgery. Otolaryngol Head Neck Surg, 136, 484-485. [38] Diamantis, T., Kontos, M., Arvelakis, A., Syroukis, S., Koronarchis, D., Papalois, A., Agapitos, E., Bastounis, E. & Lazaris, A. C. (2006). Comparison of monopolar electrocoagulation, bipolar electrocoagulation, ultracison, and ligature. Surg Today, 36, 908-13. [39] Eman, T. A. & Cuschieri, A. (2003). How safe is high-power ultrasonic dissection? Ann Surg, 237, 186-91. [40] Awwad, J. T. & Isaacson, K. (1996). The harmonic scalpel: an intraoperative complication. Obstet Gynecol, 88, 718-20. [41] Salas-Provance, M. B. & Kuehn D. P. (1990). Speech status following uvulopalatopharyngoplasty. Chest, 97, 111-117. In: Handbook of Pharyngeal Diseases... ISBN: 978-1-60876-430-3 Editors: A. P. Nazario, J. K. Vermeulen, pp. 249-262 © 2010 Nova Science Publishers, Inc.

Chapter X

Retropharyngeal Hematoma

Tun-Yen Hsu* Department of Otolaryngology, E-DA Hospital / I-Shou University, 1, Yi-Da Road, Jiau-shu Tsuen, Yan-chau Shiang, Kaohsiung County, TAIWAN, R.O.C.

Abstract

Retropharyngeal hematoma is an uncommon entity of disease of pharynx. A variety of causes are known including direct neck trauma, whiplash injury, foreign body ingestion, deep neck infection, metastatic carcinoma, anticoagulant drugs, coughing, sneezing, straining, or even spontaneous bleeding. Diagnosis can often be inferred from history but exploration may be required for confirmation. Due to pharyngeal wall swelling, it wound cause sore throat, dysphonia, dysphagia or even dyspnea while airway compromise. Physical examination may reveal stridor. In some severe cases, subcutaneous bruising over neck and anterior chest may be found. Narrowing of the pharynx can be detected simply by neck soft tissue lateral view X-ray or by endoscopic examination. Computed tomography (CT) scan or Magnetic Resonance Imaging (MRI) examination should also be necessary because the hematoma may involve inferiorly to the mediastinum causing anterior displacement of trachea or esophagus which complicate management strategy. Securing the airway is the most crucial. In traumatic cases, cervical spine immobilization is also important. Surgical evacuation of a retropharyngeal hematoma can be necessary when the hematoma is large, breathing inadequate or conservative management unsuccessful. Specific management against the possible specific cause should also be taken.

Introduction

Disease involving the retropharyngeal area is relatively uncommon. The retropharyngeal area is of potential spaces between pharyngeal wall and vertebrae

* Corresponding author: E-mail: [email protected], [email protected], Tel: +886-7-6150011-2970, Fax: +886-7-6150913 250 Tun-Yen Hsu which is composed of fatty tissue and lymph nodes. Once there is space occupying lesion in these spaces, the confining fascias will be distended anteriorly and compromise the upper as well as lower aerodigestive tracts. Therefore, dyspnea, dysphagia, sore throat or odynophagia will commence. Undoubtedly, if the volume of the space occupying lesion is so big that complete obstruction of the airway occurs, emergent airway establishment is required. The above mentioned space occupying lesion can be abscess, hematoma, enlarged lymph node or even tumor [1]. Hematoma means an abnormal localized collection of blood which is usually situated within an organ or a soft tissue space. Although retropharyngeal hematoma is an uncommon disease, the life threatening condition may sometimes be overlooked as ordinary upper respiratory tract inflammation or infection [2]. Therefore, it is worthwhile comprehensively understanding the disease.

Anatomy

There are three anatomical spaces identified between the pharyngeal wall and vertebra. The first one is retropharyngeal space which is also named posterior visceral space, is between visceral fascia and alar fascia, extending from the skull base to T4. The second one is danger space which is between alar fascia and prevertebral fascia, extending from the skull base to the diaphragm. The third one is prevertebral space which is between the prevertebral fascia and the anterior ligament of the vertebral column. The danger space provides a direct pathway for head and neck infections to spread into the posterior mediastinum. Neither the retropharyngeal space nor the danger space can be demonstrated in normal individual [1,3,4].

Etiology

Many possible causes of retropharyngeal hematoma were reported.

Neck trauma It is undoubtedly that neck trauma is one common cause of retropharyngeal hematoma [5,6,7,8]. The so-called trauma ranged from mild or blunt neck jolt [9,10,11,12,13,14,15], occipital trauma or occipital condyle fracture [16,17,18], whiplash injury [19], airbag injury [20], to many other various kinds of cervical trauma with or without cervical spine fracture [6,21,22,23,24,26,27,28,29,30,31,32,33,34, 35,36,37]. Major trauma may reasonably induce hematoma formation but how about minor blunt trauma? O‘Neill explained that this injury was caused by flexion followed by hyperextension of the cervical spine [12,38]. It was believed that formation of hematoma in cases of cervical spine trauma is from tearing of the longus colli muscles along the anterior aspect of the vertebral bodies [19]. Penning explained the injury wound cause extensive anterior ligamentous damage with rupture of larger blood vessels covering the anterior aspect of the vertebral column since the ligaments Retropharyngeal Hematoma 251 themselves area poorly vascularized and the avulsion fracture area of insignificant sizes [21].

Hemorrhagic diathesis There were two kinds of hemorrhagic diathesis were associated with retropharyngeal hematoma and were reported. One was hemophilia [39,40,41] and the other was polycythemia vera (even in general it cause a thrombotic complication)[42]. Most of them were noted to have bleeding tendency and rests of them were still associated to trauma.

Anticoagulant usage Major bleeding episodes have been reported to occur in approximately 2-4% of patients being treated with oral anticoagulants [43]. Some of the patients using anticoagulant suffered from retropharyngeal hematoma were also attributed to trauma or other causes. Anticoagulants such as warfarin [5,43,44,45,46,47,48,49], dicumarol [50,51], heparin[44], Coumadin[20,52], acenocoumarol [53] , and dipyridamol[41] were reported to be associated with retropharyngeal hematoma. Aspirin was also mentioned as a possible contributing factor because of its platelet modifying function [7,41,54,55,56,57]. In most of the cases using anticoagulants, the prothrombin time or the partial thromboplastin time were prolonged. But in some cases, the data were normal.

Neck infection Three cases of neck infection were associated with major bleeding and retropharyngeal hematoma formation [44,58,59]. It is not a common complication of neck infection but should be kept in mind.

Foreign body Three cases of foreign body were associated with retropharyngeal hematoma and were reported [60,61,62]. It is not a common complication of foreign body mis-swallowing but should also be kept in mind.

Spontaneous Spontaneous retropharyngeal hematoma is defined if there is no obvious cause such as trauma or bleeding tendency can explain the bleeding [7,8,39,57,63,64,65].

Other possible causes There are still many possible causes related to the formation of the hematoma at the retropharyngeal area: cervical arthroplasty [66], parathyroid adenoma[67,68], parathyroid cyst [69], parathyroid apoplexy [70], carotid sinus massage [71], aneurysm rupture [5,72,73], jugular vein cannulation [74], stellate ganglion block [75,76] , after vomiting [77], strain [55], sneezing [5,50], coughing [24], muscle exertion[5], turn suddenly [24], after upper respiratory tract infection [40], Epstein-Barr virus [78], and an initial presentation of metastatic prostatic cancer [79].

252 Tun-Yen Hsu

Diagnosis

History It is absolutely necessary to know the patient‘s past medical history and present illness in order to make a correct diagnosis. Because retropharyngeal hematoma is a disease affecting the upper aerodigestive tract and is acute onset, it is necessary to differentiate from some other upper aerodigestive tract emergency such as foreign body impaction, acute supraglottic laryngitis or acute epiglottitis, or deep neck infection. The common causes of retropharyngeal hematoma should be sought and even trivial trauma or minor movement should be noted. Different causes of retropharyngeal hematoma should raise different management strategies.

Symptoms Generally, due to space-occupying hematoma formation in the retropharyngeal area including retropharyngeal space, danger space, and prevertebral space, the pharyngeal wall will bulge into the pharyngeal lumen compromising the upper as well as lower aerodigestive tracts and make the patients feel sore throat, odynophagia, dysphagia, and dyspnea. Some patients may also feel neck pain and neck stiffness and therefore are unwilling to turn their neck. If the hematoma formation involves the mediastinum, the patients will feel chest pain, too. In some cases, the velocity of the hematoma formation is slow and the presentation of the symptoms may delay [6,10] . As to the patients of neck injury, we must keep in mind of the possibility of cervical spine injury.

Physical examination On examination, ecchymosis may be seen at the neck area and anterior chest (Figure 1). Due to the upper aerodigestive tract compromises, the patients may have noisy, stridulous respiration. The voice may be muffled. Tachypnea or orthopnea may also be noted.

Figure 1. Ecchymosis at anterior neck area in a patient of retropharyngeal hematoma. Retropharyngeal Hematoma 253

Endoscopic Evaluation For detailed examination, fiberoptic scope examination is performed through nasal cavity into pharynx, and it may reveal ecchymosis at the bulging posterior pharyngeal wall (Figure 2) and the degree of the upper aerodigestive tract compromise. Saliva pooling may be found. It is highly recommended to do fiberoptic scope examination either in the initial diagnosis stage or at regular following up stage because it is neither invasive nor of radiation exposure.

Radiologic evaluation The most simple and non invasive way to understand the condition of pharynx is plain X- ray evaluation. Wholey et al. had reviewed 600 normal lateral neck films and it showed that in adults (480 cases), the distance from the anterior-inferior aspect of the second cervical vertebra to the posterior wall of the pharynx should be 1–7 mm (average = 3.4mm) ; the distance from the anterior-inferior aspect of the sixth cervical vertebra to the posterior aspect of the trachea should be 9–22 mm (average = 14 mm) In children 15 years and under (120 cases), the distance from the anterior-inferior aspect of the second cervical vertebra to the posterior wall of the pharynx should be 2–7 mm (average = 3.5mm) ; the distance from the anterior-inferior aspect of the sixth cervical vertebra to the posterior aspect of the trachea should be 5–14 mm (average = 7.9 mm)[80]. Any thickness of correspondent area is larger than the normal value mentioned above should raise the suspicion of retropharyngeal disease (Figure 3). Plain X-ray evaluation should include chest X-ray film as well as neck soft tissue film because the hematoma may involve the mediastinum (Figure 4).

Figure 2. Ecchymosis at the bulging posterior pharyngeal wall in a patient of retropharyngeal hematoma. 254 Tun-Yen Hsu

Figure 3. Abnormally increased thickness of the retropharyngeal area in a patient of retropharyngeal hematoma.

Figure 4. Widened mediastinum implying hematoma involving mediastinum in a patient of retropharyngeal hematoma.

In the modern time, CT is widely available in many hospitals. CT can actually provide us anatomical change and the extension of the retropharyngeal hematoma more than plain X-ray in short time. We can know exactly the critical obstruction area in patients of retropharyngeal hematoma presenting dyspnea. However, the CT image of the retropharyngeal hematoma is not always so specific and may not aid us so much in making differential diagnosis (Figure 5). Retropharyngeal Hematoma 255

Figure 5. Mildly heterogeneously enhanced retropharyngeal swelling in a patient of retropharyngeal hematoma.

MRI is superior to CT in the diagnosis of retropharyngeal hematoma. MRI is sensitive to blood products in different stages of evolution because of the paramagnetic signal properties of the blood products which change over the time depending on their dominant component (acute deoxyhemoglobin, subacute intra- or extreacellular methemoglobin, and chronic hemichromes)[77]. The diagnosis of hematoma can be made as early as a few hours after the acute event, when hyperintensity seen on both T1- and T2- weighted sequenced [81]. However, in contrary to CT, MRI is less available and requires more patient cooperation. Patients with retropharyngeal hematoma may be agitated for dyspnea and therefore may not be suitable for MRI evaluation [77]. Angiography study is also of value in understanding the possible bleeder especially while hematoma is extensive and large vessels or their branches rupture is suspected [35].

Capps triads Capps had proposed a triad of tracheal and esophageal compression, ventral tracheal displacement on lateral cervical X-ray film and the subsequent appearance of subcutaneous bruising in the anterior neck and upper thorax which can be seen in the patients of retropharyngeal hematoma [82,83]. The triads can facilitate the diagnosis over retropharyngeal and mediastinum hematoma.

Laboratory test While facing the retropharyngeal hematoma, we should focus on those laboratory tests related to hemostasis, such as platelet count, prothrombin time, activated partial thromboplastin time or even bleeding time. Those who have history of anticoagulant usage are not necessary to have abnormal laboratory result. It is also necessary to pay attention to 256 Tun-Yen Hsu white blood cell count to help us in the differentiate infection from pure hematoma formation. Hemoglobin level and hematocrit level should also be checked to confirm whether the bleeding is severe enough to make patient anemic. Poor liver function is associated with bleeding tendency and therefore liver function test including GOT(Glutamate Oxaloacetate Transaminase), GPT(Glutamic Pyruvic Transaminase), γGT(γ- Glutamyl Transpeptidase), total bilirubin, direct bilirubin should also be performed and sonographic examination should be optionally performed if liver cirrhosis or splenomegaly are suspected. In general, unless a typical history of possible causes mentioned above such as obvious trauma, clinical diagnosis of retropharyngeal hematoma may be difficult. Usually, while facing acute onset of retropharyngeal swelling, an initial impression is either infection or tumor.

Management

It is undoubtedly paramount to pay attention to the airway. Dyspnea may be noted immediately after trauma or may be delayed in presentation even trauma is the cause of bleeding [14]. Therefore, keeping close observation is the key of management and oxygen support is absolutely given if dyspnea is noted. If ventilation is not adequate, establish a secure airway is necessary. The way to secure the airway is just like that in usual condition: either placement of endotracheal tube or tracheotomy. However, placement of endotracheal tube via oral cavity or nasal cavity may cause further pharyngeal wall trauma and may lead to bleeding into aerodigestive tract [6,38]. If intubation is still required, an anesthesiologist using fiberscope intubation technique is highly suggested and emergent tracheotomy or cricothyroidotomy should be available. In addition, it is also necessary to know whether anemia occurs and makes patients dizziness. Blood transfusion may be required. Conservative management with aspiration, observation, or medication for bleeding tendency such as Vitamin K support could be performed in minor cases. Surgical evacuation of a retropharyngeal hematoma may be necessary when the hematoma is large, breathing inadequate or conservative management unsuccessful [2]. In fact, except obvious trauma related retropharyngeal hematoma, exploration is often necessary because most of the cases of retropharyngeal hematoma are always impressed as infection or tumor initially. Only operation findings and pathological study can prove it and then other specific management against the possible specific cause should be taken accordingly. Theoretically and generally, the way to stop bleeding is locating the bleeder followed by compression, cauterization, or ligation. However, it requires surgical exploration over neck and is a relatively invasive method. On the contrary, the non-invasive method of embolization of the bleeder is possible and successful [35].

Neck trauma In neck injury patient, whether cervical spine stable or not is a crucial issue. While indicated, the patient should wear cervical collar for prevention from further cervical spine injury. In a case of severe trauma or multiple traumas, it is also necessary to pay attention to Retropharyngeal Hematoma 257 other concurrent injuries such as facial bone fracture, skull fracture with or without intracranial bleeding, clavicle fracture, rib fracture, extremities fracture, or intraabdomen bleeding which will complicate the whole condition and prolong the care time.

Hemorrhagic diathesis Hemorrhagic diathesis makes patient easy bleeding. Therefore, while patients with hemophila or other kind of hemorrhagic diatheisis, blood transfusion such as platelet or fresh frozen plasma for correction of bleeding tendency should be done. The support should be done initially and not delayed until the hematoma becomes more extensive.

Anticoagulant usage Once anticoagulant is suspiciously related to retropharyngeal hematoma, it is rationally to discontinuous the anticoagulant temporarily if no other contraindication. Component therapy is also applicable to patients with bleeding tendency for anticoagulant usage (as mentioned in the part of Hemorrhagic diathesis). Vitamin K support can be used in bleeding tendency because clotting factor II, IV, IX and X are Vitamin K dependent.

Neck infection The neck infection related retropharyngeal hematoma is often a severe condition that abscess is formation. The principle of management of such kind of neck infection is drainage of the abscess. It is reasonably to suspect that there is great vessels rupture. Be careful while exploration.

Foreign body The most important management is to remove foreign body. Because retropharyngeal hematoma existed, we should beware of whether the foreign body causes great vessels injury. In general, we can rule in or rule out this problem from CT scan. If great vessels are involved, angiography study should be performed and cardiovascular surgeon should be consulted before intervention. Possible risk should be informed.

Spontaneous As mentioned before, except obvious trauma related retropharyngeal hematoma, an initial impression is either infection or tumor. Exploration should always be done for confirming the diagnosis and for relief of tension. Therefore, except of finding out any possible causes as we can, in spontaneous retropharyngeal hematoma, we should secure the airway and control the bleeding

Other possible causes Specific management against the possible specific cause should also be taken. In the cases of parathyroid adenoma or cyst related retropharyngeal hematoma, excision is the way for diagnosis of the tumor and control the bleeding [67,68,69]. Surgical repair of the aneurysm is the key of control aneurysm rupture [5,72,73]. Epstein-Barr virus may induce hepatosplenomegaly and in consequence bleeding tendency occurs [78]. Management is the same as correct bleeding tendency.

258 Tun-Yen Hsu

Conclusion

Irrespective of any cause, retropharyngeal hematoma involves and compromises the aerodigestive tract and therefore is a life threatening problem. We should pay much attention to it and manage the near fatal condition carefully. As facing any patients in emergency, airway counts most. While securing airway or perform any other procedures, do not forget to protect the potentially fractured spine in trauma related cases. Finding out any possible cause of bleeding and correct it or repair it is the main steps we must take.

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Chapter XI

Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy and Manometry (Videfluoromanometry)

S. Cappabianca* a, L. Brunese b, A. Reginelli a, M.G. Pezzullo a, G. Gatta a, R Grassi a and A. Rotondo a aSection of Radiology, Department ―Magrassi-Lanzara‖, Second University of Naples, Piazza Miraglia 2, 80131, Naples, Italy. bDepartment of Radiology, Health Science, University of Molise, via De Sanctis, 86100, Campobasso, Italy.

Introduction

Swallowing is an essential biological function, and any alteration can determine severe consequences, such as malnutrition, dehydration, aspiration pneumonia or airway obstruction [1-2]. Swallowing disorders have a variety of causes: neurological disease, neoplasia of the oral cavity, the pharynx and/or the larynx, connective tissue disease, trauma, infection or iatrogenic illness [3-4]. Because dysphagia covers a wide range of symptoms, from a vague or subtle sensation of abnormal swallowing in an ambulatory alert patient, to a severely handicapped bedridden patient who does not seem to be able to swallow at all, a complete evaluation of the swallowing mechanism should be carried out [5-8]. Oral and pharyngeal phase dysfunctions are often due to central nervous system disorders of pyramidal and extrapyramidal pathways and peripheral nervous system motor impairment. Neurogenic dysphagia may result from cortical (generally bilateral ) lesions of the pyramidal tracts, movement disorders (for example Parkinson‘s disease), cerebellar disorders, brain stem lesions, lesion of the cranial nerves, their neuromuscular junctions or of the oral, pharyngeal or esophageal striated muscles. [9-11]. The number of swallowing impaired

* Corresponding author: Department ―Magrassi-Lanzara‖, Second University of Naples, Via Amendola 8, 81055, Santa Maria Capua Vetere, Caserta, Italy, E-mail: [email protected] 264 S. Cappabianca, L. Brunese, A. Reginelli et al. persons is substantial, particularly among the elderly. It is believed that 30% to 40% of nursing home residents have some form of swallowing impairment common in the elderly. These individuals are particularly prone to episodes of choking during swallowing, a sign that the swallowing mechanism is abnormal [12-14]. Compensatory mechanisms of the swallowing process are produced in some of these patients, either voluntary ( modifications of the diet and/or of the mechanism of swallowing) or involuntary. Especially in the elderly, the reduced sensitivity of the oral cavity, pharynx and/or larynx, and swallowing mechanism alteration, can cause aspiration or penetration of food into the trachea and bronchi, which are often not perceived by the patient, but which can lead to respiratory alterations, as laryngospasm, asthma and airway inflammation. [15]. In physiological swallowing it is possible to identify six stages [16-17].

Stage I. Preparation for Swallowing

Bolus is maintained within the mouth by close apposition of soft palate to posterior aspect of the tongue.

Stage II. Initial Stage of Swallowing

Elevation of the soft palate that is apposed to the posterior pharynx wall that moves anteriorly (Passavant‘s cushion). The anterior and downward movement of the tongue contributes to create a receiving space of the bolus in the oropharynx with initial filling of the glossoepiglottic valleculae.

Stage III. Bolus in the Oropharynx

The epiglottis tilts downward and posteriorly to prevent laryngeal injection . The superior and medium constrictor muscles of the pharynx create a posterior contraction wave (stripping wave) that pushes the bolus into the hypopharynx;. Larynx is closed and elevates during swallowing. Free up-and-down motion of larynx is an important factor preventing laryngeal injection. This elevation may be recognized by upward and anterior movement of the hyoid bone toward the mandible during deglutition

Stage IV. Bolus in the Hypopharynx

The hyoid bone and the larynx reach the maximum position. Closure of the larynx results in loss of air from the laryngeal ventricule and produces a ―conus‖ appearance with a straight inferior border of the larynx. The peristaltic wave of the constrictors pushes the bolus into the hypopharynx while the cricopharyngeal muscles are opened. Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy… 265

Stage V. Bolus in the Hypopharynx, in the Pharyngo-Esophageal Segment and Cervical Esophagus

The laryngeal vestibule remains closed from the inward fold movement of the epiglottis

Stage VI. Re-opening of the Pharynx and Larynx

All of the structures return to their initial state with the complete opening of the nasopharynx and the laryngeal vestibule and the re-opening of the larynx. Radiological contrast exame is essential to evaluate physiological swallowing dynamics and to detect pathological impairments; imaging features allow an accurate study of the tongue, palate, pharynx and larynx, providing useful information for identification of the etiology and the management planning Between different non radiological techniques - including videoendoscopy, manometry and electromyography – used in the dynamic evaluation of swallowing disorders, the videofluorographic examination allows to differentiate patients with normal swallowing from patients with swallowing alterations, which require a specific rehabilitation program. Moreover only the dynamic examination of swallowing is able to confirm or exclude the presence of aspiration or penetration of food into the airways, influencing the type of nutrition (oral/ non oral) the patient should receive. A new scenario is offered by simultaneous examination, using videofluoroscopy concurrent with solid state manometry- the videofluoromanometry [18-19]. It provides qualitative and quantitative informations by combining movement analysis with pressure recordings. This technique matches the videofluoroscopic study which is the gold standard to evaluate the bolus transit through the upper digestive tract and the manometric study which is the gold standard to assess the pharyngoesophageal motility. The informations obtained from this examination are the main route to manage the terapeuthic decisions, to program the rehabilitation program Recently, in our institution we have standardized a videofluoromanometric protocol for the assessment of oropharyngeal dysphagia, using a dedicated manometric probe specifically designed for the study of the upper GI tract/ pharyngeal tract.

Imaging Technique

The videofluoromanometric study was performed with a computerized system DYNO COMPACT (MENFIS bio MEDICA srl, Bologna, Italy) equipped with:

(1) graphics card for the management of radiological images; (2) A.VI.U.S. dedicated software, which enables the digital-quality recording (PAL/NTSC, composite video or S-Video) of videofluoroscopic images in AVI format with 320×240 resolution and 25 Hz acquisition frequency. The delay introduced by the process of image digitalization is in the order of 200 ms, so for 266 S. Cappabianca, L. Brunese, A. Reginelli et al.

analysis purposes, the images can be considered synchronized with the manometric recordings. During data acquisition, the video images are visualized on the workstation screen in real time. Videofluoroscopic study is performed with a remote-controlled commode connected to a PC workstation that allows analysis of static images and dynamic sequences and possibility of post processing elaborations. The most recent technique is digital videofluoroscopy with real time acquisition of minimum 12 images/second and a 320x240 matrix. In uncooperative patients (elderly patients with neurological disease) the examination could be performed with the patients seated rather than standing, in lateral acquisitions. [20] The following videofluoroscopic technique has been used:

Precontrastographic phase: Plain film - a preliminary soft-tissue lateral and frontal view of the neck that displays pharynx and larynx contours and provides information about the surrounding structures such as cervical vertebrae, and possible pathological conditions;

Precontrastographic dynamic phase - patient erect, frontal projection: examination of the motility of the larynx and vocal chords with a first series of acquisitions during phonation (the patient pronouncing the sound ―iii‖); - patient erect, lateral projection: examination of the motility of the soft palate (right angle lifting of the palate with apposition against Passavant‘s cushion) with a second series of acquisitions during phonation (the patient says the word ―candy‖)

Contrastographic dynamic phase - patient erect, lateral projection: examination of the oropharynx with acquisition during the swallowing of a high-density barium bolus; - patient erect, frontal projection: examination of the oropharynx with acquisition during the swallowing of a high-density barium bolus.

Boluses of small-quantity (15-20 ml) of high density ( 250% weight-volume) barium are used for the study of the oral and pharyngeal stage of swallowing. For patients suffering from dysphagia to liquids the study also includes acquisitions during swallowing of small boluses (15-20 ml) of semi-fluid barium (barium sulphate 60% weight-volume). The dynamic examinations and/or the individual frames could be examined on the same console. The simultaneous manometric evaluation was performed positioning a manometry catheter with five-channel solid state microtransducers 2 cm apart one from another and with an angle of 120°–90°. The catheter specifications and design are of critical importance since a catheter with different designs will give different values. At present no standard catheter design has been accepted. Therefore, it is important to realize that normative data must be established for the specific catheter that is used. The catheter Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy… 267 was inserted through the nasal cavity into the stomach where the value recorded was used for the calibration of 0. Afterwards, a pull through was performed, with the catheter being withdrawn to allow positioning of the transducers. The transducers have to be placed in the following positions:

1. At the level of the nasopharynx, between the tongue base and posterior pharyngeal wall 2. At the level of the proximal oropharynx. 3. At the level of the middle oropharynx. 4. At the level of the distal oropharynx. 5. In the upper esophageal sphincter (UES), with an evaluation of the correct placement with the appearance of the characteristic M-wave, confirmed also at videofluoroscopy

The manometric traces could be visualized either superimposed on the video images to maximize resolution or alongside the video images with a minimal loss in resolution. With the images alongside the manometric recordings, a cursor indicates the exact correspondence between the video images and the traces. Once the data have been acquired, data analysis is performed either in real time or at reduced or increased speed, and the images can also bepaused for a frame-by-frame analysis. The mean examination time, including catheter placement, image acquisition and compensatory manoeuvres, was estimated in 25 min, although it should be underlined that it was rarely needed to perform the full protocol because in most of times the relevant findings were early evident.

Pathological Findings

Deglutition is a complex process that involves many muscular structures and multiple innervations. Swallowing alterations are often a result of several impairments so they can appear as a complex syndrome with multiple findings rather than a single isolated dysfunction.[21] Moreover, it has to be considered that apart from pathological alteration of deglutition due to neuromuscular disorders, in all elderly people this physiological function becomes impaired because of natural aging processes, leading to a typical pathophisiologic configuration named presbiphagia.[22] Characteristic features of presbiphagia such as weakness of pharyngeal ligaments, lower position of the hyoid bone, quadrangular shape of the valleculae and expansion of the pharyngeal cavity should not be considered as abnormal findings but rather as paraphysiological aspects of an aged deglutition system. The purpose of the dynamic radiological study of the pharynx is:

1. to define normal anatomy of oropharyngeal region 2. to identify swallowing abnormalities (oral, pharyngeal phases); 3. to detect the mechanism responsible for the alteration 4. to determine the circumstances under which the patient can swallow safely. 268 S. Cappabianca, L. Brunese, A. Reginelli et al.

Figure 1. Oral incontinence. Frontal view.The incompetence of the seal between the tongue and the palate results in premature leakage (white arrows).The manometric pattern is within normal limits.

Oropharyngeal Incontinence

Drooling of saliva appears to be the consequence of a dysfunction in the coordination of the swallowing mechanism, resulting in excess pooling of saliva in the anterior portion of the oral cavity and the unintentional loss of saliva from the mouth. Incompetence of the seal between the tongue and the palate results in premature leakage of the barium into the oropharynx before initiation of swallowing with the potential for aspiration into the open, unprotect larynx (Figure 1-2).Tongue deficiency due to atrophy, weakness or uncoordination may be compensated by downward displacement of the palate with the palate ―kinking‖ to appose the tongue. [23-24]

Pharyngeal Retention

Normal subjects occasionally retain small amounts of food in the pharyngeal recesses - glossoepiglottic valleculae and pyriform sinuses- after swallowing. However, excessive retention of food in the pharynx after swallowing may be produced by obstruction of the foodway or by weakness or uncoordination of the pharynx (Figure 3).

Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy… 269

Figure 2. Oral incontinence. Lateral view. The incompetence of the seal between the tongue and the palate results in premature leakage (white arrows). The manometric pattern is within normal limits.

Figure 3. Excessive retention of barium in the pharynx (white arrow) after swallowing caused by weakness of the pharyngeal constrictor muscle. 270 S. Cappabianca, L. Brunese, A. Reginelli et al.

Pharyngeal weakness may be caused by a reduction in driving force of the tongue or weakness of the pharyngeal constrictor muscle due to nerve or muscle diseases. Residual bolus spread throughout pharynx after swallowing and enters airway as patient inhales.

Epiglottic Disfunction

Radiological examination may reveal dysfunction of the epiglottis that can assume a variety of features. A totally immobile epiglottis may lead to alterated swallowing; an epiglottis that attains an obliquity and does not tilt down properly but remains in a transverse position during deglutition, as seen in the anteroposterior projection, may lead to misdirected swallowing [25]

Penetration

Laryngeal penetration is entry of swallowed material into the larynx during swallowing, stopping at vocal cord level. It is important to distinguish laryngeal penetration from aspiration (Figure 4).

Figure 4. Laryngeal penetration. Entry of swallowed material into the larynx during swallowing, stopping at the level of the vocal cord (white arrow). No manometric remarks. Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy… 271

Figure 5. Aspiration. Entry of swallowed material through the larynx over vocal cord level (white arrow). No manometric remarks.

Aspiration

Aspiration is entry of liquid or food through the larynx over vocal cord level. Approximately 40% of patients who are aspirating are not identified during clinical evaluation. On dynamic radiological study (Figure 5), these patients are often found to have barium aspiration in the airway without coughing (silent aspiration) [26-27]. Fifty-eight percent of patients suffering from dysphagia after a stroke present aspiration of contrast bolus during the videofluoroscopic examination despite the absence of clinical symptoms [28-29]. The odds ratio of developing pneumonia is 7.6 times greater for patient who aspirate compared with those without aspiration [30]. The odds ratio of dead is 9.2 times greater for patients who aspirate thick liquids or more solid consistencies compared with those who do not aspirate or who only aspirate thin liquids. The risk of illness due to aspiration depends on several factors that can be demonstrated by radiological dynamic study as the amount and the nature of material aspirated and depth of aspiration. Laryngeal injection through the vocal cords into the trachea may occur during swallowing, prior to swallowing or after swallowing. Timing of the injection has important therapeutic implications. During radiological examination, various therapeutic modifications as will as head position, laryngeal elevation, bolus size and swallow/respiration/cough sequencing can be tried out, based on analysis of why and when aspiration occurs [31-32].

272 S. Cappabianca, L. Brunese, A. Reginelli et al.

Crycopharingeal Disfunction

Functional disturbance of the crycopharyngeal muscle makes it incapable of relaxing during swallowing. The classical finding on a dynamic radiological study is the presence of the horizontal bar (often called the cricopharyngeal bar) at the level of the C5-C6 vertebral body. This makes a posterior indentation in the barium column that persists throughout the swallow [33]. The important manometric parameters include coordination, cricopharyngeal nadir, peak amplitude clearing pressures, intrabolus pressures and special circumstances.

Coordination ("Peristalsis")

Although the use of the term "peristalsis" is objectionable by some, this term most closely describes the rapid (less than one second), orderly, sequential, antegrade pressure wave that is generated during a normal pharyngeal swallow (Figure 6). The peak amplitude clearing wave pressures, ―c waves‖, are most easily identified to evaluate "peristalsis". It is important to remember, however, that normal pharyngeal "peristalsis" is not synonymous with normal pharyngeal swallowing. Clearing wave peak pressures represent after bolus events, and as such are more accurately termed "after bolus peristalsis". "After bolus peristalsis" is one measure of pharyngeal coordination. Bolus transient in relation to pharyngeal pressures is equally important. Preswallow bolus spillage and after swallow bolus residual are easily evaluated by video fluoroscopy without manometry. However, coordination of bolus head arrival after the cricopharyngeal nadir is most easily determined by manometry and is the second critical parameter of pharyngeal coordination.

Figure 6. Coordination dysfunction. Absence of rapid (less than one second), orderly, sequential, antegrade pressure wave associated with excessive retention of barium in the pharynx and consequent entry of swallowed material into the larynx during swallowing, stopping at the level of the vocal cord. Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy… 273

Cricopharyngeal Nadir and Resting Pressures

The clinical usefulness of resting cricopharyngeal pressure measurements is so rare that precise maximal pressure measurements using slow pull-through techniques are no longer done. The resting pressure is relevant only as a base line reference point, for a given swallow and given cricopharyngeal sensor location. What is important, however, is the nadir, or lowest pressure of the cricopharyngeal sensor during the swallow and the relationship of this nadir to the bolus head. The nadir should be a negative number of -2 to -6 mm Hg using our system, and should occur prior to bolus head arrival. A negative nadir indicates normal cricopharyngeal segment relaxation and laryngeal elevation. It represents the best manometric parameter of pharyngeal shortening, laryngeal elevation. It also results in normal cricopharyngeal opening unless a fixed adynamic stricture is present. This nadir is sometimes visible, but unreliably measured on the video swallow as air in the cricopharyngeus prior to bolus arrival

Maximum Amplitude Clearing Pressures

Besides their importance in determining peristalsis, maximum amplitudes of the post swallow clearing waves are indicators of pharyngeal strength. These peak amplitude pressures of the tongue base, hypopharynx, and cricopharyngeus regions are simple, easily determined values that objectively quantify pharyngeal strength. The correlation of these peak amplitudes with subjective "impressions" determined by videofluoroscopy is excellent. Terms such as mild, moderate, and severe can be replaced by objective numbers such as 60- 75 mm Hg, 40-60 mm Hg, and <35 mm Hg, respectively. (Normal = 80-120 mm Hg.)

Intrabolus Pressures

The third, perhaps most important, and yet most difficult, manometric pressures to evaluate are intrabolus pressures. Liquid intrabolus pressures are indicators of, but are not synonymous, with, intrabolus propulsive forces, assuming antegrade movement. Elevated intrabolus pressures indicate outlet obstruction. However, the opposite, outlet obstruction results in elevated intrabolus pressures, may not be true for two reasons. One, if the structures doing the pushing (tongue base, hypopharynx) are so weak they are incapable of generating elevated intrabolus pressures, or two, coordination is lacking and bolus movement is not antegrade. The amplitude and sequential timing of the peak clearing pressures are therefore important to assess prior to determining intrabolus pressures. In the presence of weak but coordinated driving forces (i.e., decreased clearing wave peak amplitudes and decreased laryngeal elevation, as is commonly seen in many dysphagic patients), the evaluation of outlet obstruction is difficult.

274 S. Cappabianca, L. Brunese, A. Reginelli et al.

Delayed and Incomplete Opening of the Cricopharyngeus Muscle

Thanks to manometric evaluation, the term cricopharyngeal achalasia, often used to designate insufficient or delayed relaxation of the cricopharyngeal muscle during swallowing (2,11 ), seems inappropriate, since achalasia means ―not relaxing‖ and in these patients the muscle does relax, even if delayed or incomplete(Figure 7),. Cricopharyngeal dysfunctions seems to be a more adequate designation [34].

Figure 7. Crycopharyngeal dysfunction. In this patient the muscle does relax, even if in a incomplete way (red arrow) with retention of barium in the pharynx (white arrow).

Manometry alone identified a higher percentage of subjects with a swallowing disorder but was less precise in classifying the swallowing phase affected. A standardized manometric technique is important in videofluoromanometry, and normal values as described in this study are essential in clinical use. The results of two evaluations ( radiologic and manometric) taken separately produced a diagnosis of dysphagia in approximately the same percentage of cases , although with several differences in the subcategories of swallowing disorders and patients.

Conclusion

The role of the diagnostic imaging is essential in the depiction of the morphofunctional abnormalities of the upper digestive tract thanks to the possibilities offered by the dynamic imaging and the combined imaging. Radiologic contrast examination is essential to evaluate physiologic swallowing dynamics and to detect pathologic impairments. Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy… 275

Various nonradiologic techniques, including videoendoscopy, manometry, and electromyography, are used in the dynamic evaluation of swallowing disorders. Simultaneous videofluoroscopy (barium swallow) provides fluoroscopic control of the manometric sensors. (videofluoromanometry), thereby eliminating the uncertainty of sensor dislocation during laryngeal elevation. Only through the dynamic examination of swallowing is it possible to confirm or exclude the presence of food aspiration or penetration into the airways; this information influences the type of nutrition (oral or parenteral) the patient should receive. Simultaneous examination using videofluoroscopy concurrent with solid statemanometry—videofluoromanometry— provides qualitative, and quantitative information by combining movement analysis with pressure recordings. Videofluoromanometry is the study of choice in dysphagic or suspected dysphagic patients because it joins the advantages of the dynamic visualization of swallowing with the functional data acquired with the simultaneous recording of the pressure variations at different levels in the pharynx and esophagus.. The technical problems of catheter positioning for the manometric study of the pharynx (UES opening, breathing, catheter movements) are resolved with the visualization of the anatomical structures offered by the fluoroscopy, that allows the correct positioning during the various study phases. The technique was first described by Sokol et al in 1966, with perfusion catheters. In 1988, McConnel et al introduced the solid state transducers with high-frequency response. This technique was confirmed by Castell et al in 1990 and by Olsson at al in 1995 When used simultaneously, videofluoroscopy and manometry are able to evaluate causes and effects of pharyngeal dysfunction that cannot be examined by each of the techniques individually. Moreover, the aetiology of oropharingeal dysphagia is not always correctly detected even after clinical, biochemical and radiological examinations- including magnetic resonance imaging. The use of the combined technique enables the diagnosis of neurological damage in patients with dysphagia sine causa and at the same time it may suggest a conservative or operative treatment (cricopharyngeal muscle dilatation, myotomy, botulin injection) in patients with dysphagia of certain neurologic origin. Videofluoromanometry represents the new scenario for assessment and management of the swallowing disorders and the main limitations for the wide diffusion of the technique are due to the significant initial costs of the instrumentation (up to $ 30 000) and to the training period required for the physicians. The learning curve, however, is inversely proportional to the experience of any single operator and it could be estimated in 8-10 procedure under supervision of an expert personnel. Videofluoromanometry is a clinically useful tool that should not routinely replace the standard modified barium swallow. Its use should be selective for difficult or unusual patients. In these patients, establishing treatment plans, whether surgical or non-surgical, is often greatly facilitated by the addition of manometry to the video swallow. Manometry quickly and simply adds a crucial objective parameter to swallowing evaluations when done both before and after treatment. Manofluorography provides important additional information to the modified barium swallow that does not define the etiology of dysphagia but rather the therapy of the dysphagia.

276 S. Cappabianca, L. Brunese, A. Reginelli et al.

References

[1] Bartz, S. (2003). Gastrointestinal Disorders in the Elderly Annals of Long-Term Care, Clinical Care and Aging, 11[7], 33-39. [2] Grassi, R. (2003). Diagnostic imaging of deglutition and continence-defecation disorders. Radiol Med, Sep, 106(3 Suppl. 1), 90-3. [3] Bryan, D. (2005). Abdominal pain in elderly persons e-medicine, 5 Oct. [4] Amjad, N. (2003). Acute Abdomen In The Elderly – A Diagnostic Dilemma. IN: e-imj, June, Vol 2., No 1. [5] Jones, B. & Donner, M. W. (1988). Examination of the patient with dysphagia. Radiology, 167, 319-326 [ Erratum in Radiology 1991;179: 881]. [6] Ott, D. J. & Pikna, L. A. (1993). Clinical and videofluoroscopic evaluation of swallowing disorders. AJR, 161, 507-513. [7] Lind, C. D. (2003). Dysphagia: evaluation and treatment. Gastroenterol Clin North Am, 32, 553-575. [8] Reginelli, A. & Pezzullo, M. G. (2008). Gastrointestinal Disorders in Elderly. Radiol Clin N Am, 46, 755-771. [9] Chaundhry, V. (2000). Neurogenic Dysphagia – Basics. Records of eighth multidisciplinar symposium on dysphagia. ohns Hopkins Medicine. Baltimore. [10] Barbiera, F., Iacono, G., Carroccio, A., et al. (2004). Digital cineradiographic study of swallowing in infants with neurologic disease. Our experience. Radiol Med, 107, 286- 292. [11] Hamdy, S. (2004). The diagnosis and management of adult neurogenic dysphagia. Nurs Times, 100, 52-54. [12] Kendall, K. A. & Leonard, R. J. (2002). Videofluoroscopic upper esophageal sphincter function in elderly dysphagic patients. Laryngoscope, 112, 332-337. [13] Feinberg, M. J. & Ekberg, O. (1990). Deglutition after near-fatal choking episode: radiologic evaluation. Radiology, Sep, 176(3), 637-40. [14] Tracy, J. F., Logemann, J. A., Kahrilas, P. J., et al. (1989). Preliminary observations on the effects of age on oropharyngeal deglutition. Dysphagia, 4(2), 90-4. [15] Feinberg, M. J. & Ekberg, O. (1991). Videofluoroscopy in elderly patients with aspiration: importance of evaluating both oral and pharyngeal stages of deglutition. AJR Am J Roentgenol., Feb, 156(2), 293-6. [16] Jones, B. & Donner, M. W. (1991). Normal and Abnormal Swallowing. Springer Verlag, NewYork, 77-8.Dodds, W. J., Stewart, E. T. & Logemann, J. A. (1990). Physiology and radiology of the normal oral and pharyngeal phases of swallowing. AJR Am J Roentgenol., May, 154(5), 953-63. [18] Olsson, R., Castell, J., Johnston, B., et al. (1997). Combined videomanometric identification of abnormalities related to pharyngeal retention. Acad Radiol., May, 4(5), 349-54. [19] Cappabianca, S. & Reginelli, A. (2008). Combined videofluoroscopy and manometry in the diagnosis of oropharyngeal dysphagia: examination technique and preliminary experience. Radiol. Med., May, 4(5), 349-54. Pharyngeal Disorders: Diagnosis with Combined Videofluoroscopy… 277

[20] Feinberg, M. J., Ekberg, O., Segall, L., et al. (1992). Deglutition in elderly patients with dementia: findings of videofluorographic evaluation and impact on staging and management. Radiology, Jun, 183(3), 811-4. [21] Barbiera, F., Fiorentino, E., D'agostino, T., et al. (2002). Digital cineradiographic swallow study: our experience. Radiol Med (Torino), Sep, 104(3), 125-33. [22] Ekberg, O. & Feinberg, M. J. (1991). Altered swallowing function in elderly patients without dysphagia: radiologic findings in 56 cases. AJR Am J Roentgenol., Jun, 156(6), 1181-4. [23] Chen, M. Y., Ott, D. J., Peele, V. N., et al. (1990). Oropharynx in patients with cerebrovascular disease: evaluation with videofluoroscopy. Radiology, 176, 641-643. [24] Dodds, W. J., Taylor, A. J., Stewart, E. T., et al. (1989). Tipper and dipper types of oral swallows. AJR Am J Roentgenol., Dec, 153(6), 1197-9. [25] Ekberg, O. (1983). Epiglottic dysfunction during deglutition in patients with dysphagia Arch Otolaryngol., Jun, 109(6), 376-80 [26] Schmidt, J., Holas, M., Halvorson, K., et al. (1994). Videofluoroscopic evidence of aspiration predicts pneumonia and death but not dehydration following stroke. Dysphagia, 9, 7-11. [27] Pikus, L., Levine, M. S., Yang, Y. X. et al. (2003). Videofluoroscopic studies of swallowing dysfunction and the relative risk of pneumonia. AJR Am J Roentgenol, 180, 1613-1616. [28] Horner, J., Massey, E. W., Riski, J. E., et al. (1988). Aspiration following stroke: clinical correlates and outcome. Neurology, 38, 1359-1362. [29] Paciaroni, M., Mazzotta, G., Corea, F. et al. (2004). Dysphagia following stroke. Eur Neurol, 51, 162-167. [30] Upadya, A., Thorevska, N., Sena, K. N., et al. (2004). Predictors and consequences of pneumonia in critically ill patients with stroke. J Crit Care, 19, 16-22. [31] Curtis, D. J. & Hudson, T. (1983). Laryngotracheal aspiration: analysis of specific neuromuscular factors. Radiology, 149, 517-522. [32] Rasley, A., Logemann, J. A., Kahrilas, P. J., et al. (1993). Prevention of barium aspiration during videofluoroscopic swallowing studies: value of change in posture. AJR Am J Roentgenol, 160, 1005-1009. [33] Ekberg, O. & Nylander, G. (1982). Dysfunction of the cricopharyngeal muscle. A cineradiographic study of patients with dysphagia. Radiology, 143, 481-486. [34] Olsson, R. & Nilsson, H. (1995). Simultaneous videoradiography and pharyngeal solid state manometry (videomanometry) in 25 nondysphagic volunteers. Dysphagia, Winter, 10(1), 36-41.

Chapter XII

Treatment of Cervical Fistulae after Microsurgical Reconstruction Following Radical Ablation of Head and Neck Cancers

Masaki Fujioka* Department of Plastic and Reconstructive Surgery, National Nagasaki Medical Center, Nagasaki, Japan.

Abstract

Background

Cervical fistulae caused by unsuccessful wound healing after microsurgical reconstruction are sometimes seen in patients who have undergone radical ablation of head and neck malignancies. They can cause long-term distress for the patient and decrease their quality of life. Furthermore, treatment of fistulae is challenging because these patients have often undergone radiotherapy.

Methods

We reviewed the records of 83 patients with head and neck cancer who required radical resection and microsurgical reconstruction in our unit from 2004 through 2007. Among these patients, 11 developed cervical fistulae postoperatively. We investigated the associations between radiotherapy, chemotherapy, tumor size, lymph node metastasis, and type of flaps and the development of postoperative fistulae.

* Corresponding author: Department of Plastic and Reconstructive Surgery, National Hospital Organization Nagasaki Medical Center, 1001-1 Kubara 2 Ohmura city,Japan Zip 856-8562, Tel.: 0957-52-3121, Fax.: 0957-54-0292, E-mail: [email protected] 280 Masaki Fujioka

Results

All 11 patients who developed cervical fistulae had undergone radiotherapy, which was identified as the most important risk factor for postoperative cervical fistulae. All the fistulae were successfully treated with a pectoralis major musculocutaneous flap.

Conclusions

Cervical fistulae that occurred after radiotherapy and microsurgical reconstruction do not heal spontaneously despite aggressive medical wound management. Skin grafts and local cutaneous flaps harvested from within the radiation field are unreliable and rarely provide adequate and stable coverage. Salvage surgery using a musculocutaneous flap is recommended to facilitate healing of these complex wound.

Keywords: Cervical fistulae, radiotherapy, musculocutaneous flap, salvage surgery.

Introduction

Reconstruction of defects in the head and neck region has remained a challenging problem for craniofacial, plastic, and head and neck surgeons. [1] Cervical skin flaps have been utilized in head and neck reconstruction from the time they were originally described, more than 100 years ago; and later, axial pattern flaps were developed. [2,3,4] However, the use of these flaps, particularly, in esophageal reconstruction, has declined because pedicled flaps do not provide of sufficient tissue volume and proper texture. [3] As the familiarity and reliability of microsurgical reconstruction has increased, free tissue transfer has become the preferred surgical method for head and neck reconstruction; however, unfavorable complications such as wound dehiscence, infection, hematoma, seroma, flap failure, and fistula still occur. [5.6,7, 8] In this article, 11 cases of cervical fistulae after free flap reconstruction for tumors of the head and neck were investigated to determine the factors responsible for the occurrence of postoperative cervical fistulae. The superior results obtained with salvage surgery using a musculocutaneous flap for the treatment of complex cervical fistulae are also presented.

Patients and Methods

We examined the records of 83 patients with head and neck cancers who underwent radical resection and microsurgical reconstruction in our unit from 2004 through 2007. Ages ranged from 26 to 82 years (mean age, 62.1 years). Among these patients, 11 developed postoperative cervical fistulae. They ranged in age from 38 to 82 years (mean age, 62.6 ± 13.4 years); patients without cervical fistulae ranged in age from 26 to 80 years (mean age, 61.8 ± 12.2 years) (no significant difference, Wilcoxon rank sum test). We investigated the associations between postoperative fistulae and tumor tumors, lymph node metastasis, and type of flap radiotherapy, chemotherapy. Statistical analysis was performed using the t test. Cervical Fistulae after Microsurgical Reconstruction 281

Table: Characteristics of patients who developed cervical fistulae.

Patient Se Ag Original TMN Radiation Woun Secondar Primary surgery Period from Chemo- numbe x e disease pathology (Gy) d size y surgery radiotherapy therapy r (cm) to primary surgery 1 Ｍ 65 Hypopharyngea pT2N0M0 68 4×3 PMMC TPLE, NR 70 months l cancer SCC preoperative flap Free jejunum flap transfer 2 M 82 Mesopharyngea pT4N2M0 66 3×3 PMMC TPLE, NR 6 months - l cancer SCC preoperative flap Free jejunum flap transfer 3 M 76 Mesopharyngea pT3N0M0 66 3×3 PMMC Partial 32 months - l cancer SCC preoperative flap mesopharyngectomy, (recurrent) NR Free ALTflap transfer 4 M 57 Hypopharyngea pT2N0M0 65 5×4 PMMC TPLE, NR 11 months CDDP10 l cancer SCC preoperative flap Free jejunum flap 0 mg, (recurrent) transfer 5Fu 500 mg 5 M 64 Laryngeal pT2N0M0 60 2×2 PMMC TPLE, NR 10 months - cancer SCC preoperative flap Free jejunum flap (recurrent) transfer 6 M 64 Laryngeal pT4N2M0 66 2×2 PMMC Partial laryngectomy, 12 months - cancer SCC preoperative flap NR (recurrent) Free forearm flap transfer 7 M 58 Laryngeal pT2N0M0 44 2×2 PMMC Total laryngectomy, 13 months - cancer SCC preoperative flap NR (recurrent) Free RAMC flap transfer 8 M 81 Metastatic pTXN2cM 60 5×4 PMMC TPLE, NR 6 months - laryngeal cancer 0 preoperative flap Free jejunum flap SCC transfer

9 M 55 Mesopharyngea pT3N2bMo 70 2×2 PMMC Partial 3 months - l cancer SCC postoperativ flap mesopharyngectomy, (1M after e NR radiation) Free RAMC flap transfer 10 M 38 Mesopharyngea pT2N2M0 60 5×3 PMMC Partial 2 months - l cancer SCC postoperativ flap mesopharyngectomy, (1M after e NR radiation) Free RAMC flap transfer 11 F 49 Epipharyngeal pT4N2M0 60 5×2 Free Partial 3 months CDDP10 cancer SCC preoperative RAMC epipharyngectomy,N (2M after 0 mg (recurrent) flap R radiation) Free forearm flap transfer

SCC, Squamous cell carcinoma. LD MC flap, latissimus dorsi musculocutaneous flap. PM MC flap, pectoralis major musculocutaneous flap. TLPE, Total laryngo-pharyngo-esophagectomy. NR, neck resection. RAMC flap, rectus abdominal musculocutaneous flap. ALTflap, anterolateral thigh flap. CDDP, Cisplatin.

Results

Eleven patients developed cervical fistulae postoperatively. Their profiles and clinical parameters including, sex, age, original disease, staging and pathological diagnosis, radiation, wound size, primary and secondary surgery, the interval between radiotherapy to the development of the fistula, and chemotherapy regimen are shown in the Table.

282 Masaki Fujioka

(1) The association between tumor classification and incidence of fistulae was investigated. All neck cancer patients classified as M0 underwent surgery. A total of 5 of 69 patients (7.2 %) who underwent treatment for primary cancer, and 6 of 14 patients (42.9 %) who underwent treatment for recurrent cancer, developed fistulae (Figure 1). (p<0.01, t test). The association between tumor size and incidence of fistulae is shown in Figure 2. Four of 41 patients (9.8 %) with T4 tumors, and, 4 of 22 patients (18.2 %) with T2 tumors, developed fistulae. These results suggest that larger tumor size is not associated with postoperative cervical fistulae. The association between lymph node metastasis and incidence of fistulae is shown in Figure 3. Although fistulae did not occur in any in N3 or N1 patients, they did occur in 6 of 42 (14.3 %) N2 patients, and in 5 of 33(15.1 %) N0 patients. These results suggest that the extent of lymph node metastasis is not associated with the development of postoperative cervical fistulae.

Figure 1. Fistulae in patients with primary and recurrent cancer.

Figure 2. Tumor size in patients with and without neck fistulae. Cervical Fistulae after Microsurgical Reconstruction 283

Figure 3. Lymph node metastasis in patients with and without neck fistulae.

Figure 4. Reconstructive technique in patients with and without cervical fistulae.

Figure 5. Radiotherapy status in patients with and without cervical fistulae. 284 Masaki Fujioka

(2) The association between reconstructive technique and the development of fistulae is shown in Figure 4. Fistulae developed in 2of 7 patients (28.6 %) after free skin flap transfer, in 5 of 32 cases (15.2 %) after free jejunum flap transfer, in 1 of 8 (11.1 %) after free fasciocutaneous flap transfer, in 3 of 33 (9.1 %) after free muscurocutaneous flap transfer, and 0 patients after use of a free bone flap transfer. Neck reconstructions with thinner flaps were slightly more likely to result in cervical fistulae; however, the difference was not statically significant. (3) The association between radiotherapy and the development of fistulae is shown in Figure 5. A total of 11 of 35 (31.4 %) patients who underwent radiotherapy developed cervical fistulae: among the 48 patient who did not undergo radiotherapy, none developed. There was a significant difference between these subgroups (p<0.001, chi-square test). Among the 35 irradiated patients, 8 of 13 (61.5 %) underwent radiation treatment before undergoing primary surgery, and 3 of 22 (13.6 %) did so immediately after primary surgery (Figure 6). There was a significant difference between these subgroups (p<0.05, Cchi-square test).

Figure 6. Time of radiotherapy administration in irradiated patients with and without fistulae.

Figure 7. Chemotherapy status in patients with and without cervical fistulae. Cervical Fistulae after Microsurgical Reconstruction 285

(4) The association between chemotherapy and the development of fistulae is shown in Figure 7. Fistulae occurred in 9 of 68 (13.2 %) of patients, who underwent chemotherapy and in 2 of 15 (13.3 %) patients, who did not. There was no significant difference between these subgroups (p>0.3, chi-square test).

Discussion

1. The History and Techniques of Neck Reconstruction

Reconstruction of head and neck defects following cancer ablation is extremely challenging. The amount of tissue loss may be extensive and tissue destruction may involve heterogeneous elements. It is important to consider both the functional and aesthetic aspects of reconstruction while planning the procedure. [1] Resurfacing with skin grafts, i.e. the transfer of a portion of the skin (without its blood supply) to the wound, for massive tissue defects of the head or neck resulted in a 100 % complication rate and defined as the need for further surgery, because such grafts are too thin and too weak to protect important structures such as the carotid vessels and cranial nerves. In the past, head and neck reconstruction for facial and cervical cutaneous defects had been performed by means of compound local cervical flaps, which are transferred with their original blood supply (Figure 8a-d). [2, 4] However, local flaps also resulted in a high rate of complications because these flaps, which were usually located at the edge of the ulcer, were within the radiation field and often too small to adequately reconstruct a defect after tumor ablation.[9] The development of axial pattern flaps with rich blood flow, is a technical improvement that reduces the rate of postoperative complications in head and neck reconstruction, and has therefore been widely utilized (Figure 9a-c). [10,11] However, 60% of head and neck reconstructions that use the pectoralis major myocutaneous pedicled flap, which is the most commonly indicated procedure, result in postoperative complications such as wound dehiscence, infection, hematoma, seroma, partial flap failure, total flap failure, and fistula.[3] Application of microvascular free tissue transfer, which involves the transfer of detached blood vessels that are attached at the site of the wound, allows the surgeon to select the tissue that is most suitable for the size and shape of defect. Consequently, the incidence of flap complications is reduced to 33.5% of that of free flaps. [8] Free flaps can be utilized for the reconstruction of mid-upper facial defects, including the scull base, scalp, orbit, maxilla, and palate, all of which are hard to restore using conventional pedicle flaps.[12, 13] with greater experience in microsurgical reconstruction and the availability of a larger number of flaps, free tissue transfer has become common and reliable. Indeed, it is now a standard technique for the head and neck reconstruction after tumor ablation (Figure 10, 11, 12). [5, 6, 7, 14].

286 Masaki Fujioka

(a) (b)

Figure 8. (a) A photograph of laryngeal cancer invading the skin of the neck. (b) A photograph taken after the neck tumor was excused shows the design of the random pattern skin flap. (c) Anntraoperative photograph shows elevation and rotation of the skin flap. (d) The photograph shows the reconstructed wound one month after surgery. Cervical Fistulae after Microsurgical Reconstruction 287

(a) (b)

(c)

Figure 9. (a) A photograph of a fistula on the neck, resulting from laryngeal cancer. (b) The photograph shows a pectoralis major muscle flap being elevated and rotated toward the neck. The flap remained attach to the donor site by a feeding artery. (c) The photograph shows the reconstructed wound 1 month after surgery.

288 Masaki Fujioka

(a)

(b)

(c)

Figure 10. (a) The photograph shows removal of the tongue and oral floor to treat of lingual cancer. (b) The photograph shows the free anterolateral thigh flap being elevated and detached from its original location. (c) The photograph shows the reconstructed tongue and oral floor after microsurgical free flap transfer.

(a) (b) Cervical Fistulae after Microsurgical Reconstruction 289

Figure 11. (a) The photograph shows an intraoperative view of a total laryngo-pharyngo-esophagotomy for the treatment of carcinoma of the larynx. (b) The photograph of the harvested jejunum flap. (c) The photograph of the free jejunum flap, which is inserted and anastomosed with the esophagus and pharynx. (d) Pharyngeal fluoroscopy 1 month after surgery confirmed that the patient was able to ingest a barium meal without backflow or leakage.

2. Frequency, Degree and Course of Cervical Fistulae after Neck Reconstruction

Despite the benefits associated with microvascular free tissue transfer, a small chance of failure remains. On such complication, postoperative fistulae, can cause long-term distress for the patient, delay initiation of oral intake, increase hospitalization time, and, consequently, decrease patient quality of life.

(a) (b) 290 Masaki Fujioka

(b)

(c)

Figure 12. (a) An intraoperative photograph showing the treatment of parotid cancer with neck lymph node and skin metastasis. A wide soft tissue defect is present. (b) The photograph shows the resurfacing of the neck wound using a free rectus abdominis flap transfer. (c) The photograph of patient 6 months after surgery. Facial nerve palsy was treated by static suspension.

Pharyngocutaneous fistula is the most common complication (8.7% to 22%) during the immediate postoperative period after total laryngectomy. [15-17] Redaelli et al. reviewed the clinical course of 39 of 246 (16 %) patients who developed cervical fistulae after total laryngectomy for squamous cell carcinoma. Among these patients, spontaneous closure with local wound care was achieved within 3 weeks in 70% of cases. [18] Saki et al. examined 19 patients who developed cervical fistulae after total laryngectomy and reported that most fistulae could be successfully managed with conservative treatment. [19] These patients experienced satisfactory wound healing, without secondary surgery, because they underwent only laryngectomy; nearly all of these patients did not undergo reconstruction using free flap transfer. Bozikiv and Arnez reported the occurrence of cervical fistulae following restoration with free flaps in 12 of 194 (6.2%) cases. [8] In the present study, among patients who underwent reconstruction with free flaps, 11 of 83 (13.2%) with cervical fistulae required salvage surgery, which suggests that the frequency of cervical fistulae after reconstruction with free flaps is similar or inferior, to that of procedures using conventional flaps. Depending on the characteristics of the severances, reconstruction using free fraps appears to cause more severe cervical fistulae, as indicated by the need for second surgeries. However, radical and wide tumor ablation, such as that required for a total laryngo-pharyngo-esophagectomy, requires free flaps to repair the extensive tissue loss. As a result, development of cervical fistulae after reconstruction with free flaps tends to be more severe because this reconstructive technique is likely to be used for the treatment of more severe cancer cases. Cervical Fistulae after Microsurgical Reconstruction 291

3. Risk Factors for Postoperative Neck Fistulae after Microsurgical Reconstruction

It is commonly believed that the development of postoperative neck fistulae after surgical reconstruction is influenced by several underlying factors, including the presence of systemic diseases, previous radiotherapy, chemotherapy, positive surgical margins, and lymph node metastases. [16-21] However, we observed that putative several risk factors for conventional flap reconstruction, including extent of lymph node metastasis and use of chemotherapy, were not associated with fistulae when reconstruction was performed with free flaps. Furthermore, tumor size to be removed was not a risk factor, because free flaps of any size or any type of tissues, could be harvested. In addition, the ability to reconstruct larger areas permits the more radical ablation of malignant tumors, which reduces the rate of positive surgical margins-one of the risk factors for postoperative cervical fistulae. There are many conflicting reports concerning the predisposing factors for postoperative cervical fistulae after flee flap reconstruction, but our data show that radiotherapy is the most important. The combination of endarteritis and chronic ischemia caused by radiation interrupt the normal process of wound healing, consequently, develop cervical fistulae. Pinar E et al. also reported that 12 percent of 33 free flap transfers after irradiation remained fistula formation. [20] The lack of contraction caused by delayed myofibroblast function, and repeated wound contamination are also factors of non-improvement in irradiated wound. [9, 10, 22].

4. Salvage Surgery for Cervical Fistulae Developing after Radiotherapy

At a minimum, flaps are required to treat cervical fistulae. Skin grafts are not indicated, because a previously irradiated wound bed does not have a sufficient oxygen and nutrient supply. [10, 23] Elevation of local flaps is also not recommended because tissue surrounding the ulcer crater has often been compromised by radiotherapy, which result in the loss of at least part of the flap. [9] With the development of axial-pattern musculocutaneous and muscle flaps, it is less difficult to deal with these ulcers. [10, 11] Surgeons can now recommend earlier debridement of the entire irradiated area, followed by immediate coverage with a well vascularized axial-pattern musculocutaneous flap or revascularized free flap. [24] When irradiated wounds increase in size, complete excision of the wound requires a well- vascularized distant flap. [25, 26] Strawberry reported that only 6 of 52 patients with cervical irradiation ulcers could be successfully treated with either local skin flaps or a free skin graft; the remaining 46 patients required the use of myocutaneous flaps and including pectoralis major musculocutaneous flaps, latissimus dorsi musculocutaneous flaps. [10] The use of a pectoralis major musculocutaneous flap remains an important reconstructive technique in head and neck cancer surgery, because it is a with low-risk procedure with acceptable morbidity. [27] In addition, this flap can be still used in a salvage procedure after free flap failure or when there facility with microsurgery is limited. [3] The pectoralis major muscle originates from the medial part of the clavicle, the sternocostal border of the first 6 ribs, and the external oblique muscle aponeurosis. The main 292 Masaki Fujioka functions of the muscle are adduction and medial rotation of the arm. Sacrifice of this muscle leads to only minimal functional deficit because adjunct muscles of the shoulder belt can almost completely compensate for the loss. [28] The pectoralis major muscle and its overlying skin receive their blood supply from the pectoral branch of the thoracoacromial vessels originating from beneath the midportion of the clavicle. The skin island should be centered over the pectoralis major muscle. When the flap is elevated completely as a vascularized island flap, it can reach cervical fistulae easily. This safe and reliable flap is our first choice for salvage surgery after unfavorable outcomes for free flap reconstruction, including development of cervical fistulae. Below, we describe our successful results with pectoralis major MC flaps for the treatment of complex cervical fistulae (Figure 13).

Figure 13. Schema of a pectoralis major musculocutaneous flap.

5. Representative Cases of Salvage Surgery for Cervical Fistulae after Radiation Treatment and Free Flap Reconstruction

Case 1. A 49-year-old woman received a total dose of 60 Gy during radiotherapy for epipharyngeal squamous cell carcinoma, 1 month after ablation of the tumor and reconstruction using free forearm flap transfer. A contaminated neck ulcer measuring 2×2 cm, which formed fistula that penetrated to the oral floor, occurred 3 months after surgery (Figure 14a). Chronic dermatitis and a small skin ulcer around the fistula that had been caused by radiation treatment were also observed on the neck. Oral examination showed a fistula connecting to the neck ulcer (Figure 14b). The cervical fistula and cavity involving the irradiated skin were widely debrided and the defect was reconstructed using a pectoralis major musculocutaneous flap (Figure 14c). Immediately after surgery, the patient was able to orally ingest a soft diet without backflow or leakage, and the patient was discharged, without relapse of fistula, 2 weeks after surgery. Cervical Fistulae after Microsurgical Reconstruction 293

(a) (b)

(c)

Figure 14. (a) Case 1. A photograph of a cervical fistula in patient who underwent treatment with 60 Gy of radiation and ablation of tumor for epipharyngeal SCC. Reconstruction surgery utilizes a free forearm flap. (b) The photograph shows a fistula connecting to the neck ulcer (arrow). (c) An intraoperative photograph. The radiation ulcer and cavity were debrided and reconstructed using a pectoralis major musculocutaneous flap.

294 Masaki Fujioka

(a) (b)

(c)

Figure 15. (a) Case 2. A photograph of a cervical fistula in a patient who underwent treatment with 65 Gy of radiation, ablation of tumor, and reconstruction using a free jejunum flap for hypopharyngeal SCC. (b) An intraoperative photograph of the secondary surgery shows insertion of the transported pectoralis major muscle into the fistula to occupy the dead space. (c) The photograph shoes the reconstruction of cervical fistula.

Case 2. A 65-year-old man received a total dose of 65 Gy during radiotherapy for hypopharyngeal squamous cell carcinoma. Eleven months later, a recurrent tumor developed, and the patient underwent ablation of the tumor and reconstruction using a free jejunum flap transfer. However, a contaminated cervical fistula measuring 5×4 cm occurred 1 month after surgery (Figure 15a). Chronic dermatitis around the fistula due to radiation treatment was also observed on the neck. The cervical fistula and cavity involving the irradiated skin were widely debrided and the defect was reconstructed using a pectoralis major musculocutaneous flap. The transported muscle body was inserted into the fistula to occupy the dead space (Figure 15b, 15c). The patient was able to orally ingest a soft diet without backflow or leakage immediately after surgery, and was discharged without a relapse of the fistula, 3 weeks after surgery. Cervical Fistulae after Microsurgical Reconstruction 295

(a) (b)

(e)

Figure 16. (a) Case 3. A photograph of a patient who had received 68 Gy of radiation for the treatment of hypopharyngeal SCC 14 years before. The chronic cervical fistula is visible. (b) A CT image shows the dead space between the vertebrae and transported jejunum flap (A) and an abscess in the cervical spinal canal (B). (c) An intraoperative photograph shoes a fistula leading to the anterior surface of the cervical spine; a contaminated, infected anterior longitudinal ligament is exposed. (arrow). (d) An MRI 7 days after surgery shows the pectoralis major muscle flap placed over the surface of the vertebral bodies (A), as well as inflammatory granulation in the spinal canal (B). (e) An MRI 5 months after surgery confirms that the disappearance of the epidural abscess. 296 Masaki Fujioka

Case 3. A 64-year-old man who had undergone radiation therapy for treatment of pharyngeal cancer 14 years before, underwent total laryngo-pharyngo-esophagotomy for the treatment of a recurrence. After ablation of the malignant tumor, a free jejunum flap was transferred. Three days later, the patient developed a fever with purulent discharge from the neck wound, even though the circulation in the transferred jejunum flap was satisfactory (Figure 16a). Magnetic resonance imaging (MRI) revealed an abscess in the spinal canal and a deformity of the vertebral bone, which suggested cervical osteomyelitis (Figure 16b). Radical excision of the infectious tissues was performed. The anterior surfaces of the contaminated vertebral bone bodies between C4 and C6 were osteotomized, and a vascularized pectoralis major muscle flap was placed over the surface of the vertebral bodies (Figure 16c, 16d). The patient was discharged without tetraplegia, neck instability, or relapse of infection, 8 weeks after surgery. An MRI 5 months after surgery confirmed the disappearance of the epidural abscess and favorable vertebral alignment (Figure 16e).

Conclusion

With increased experience in microsurgical reconstruction, free tissue transfer has become a standard technique in head and neck reconstruction after tumor ablation. However, patients receiving radiation treatment are more likely to develop cervical fistulae when they undergo reconstructive surgery with free flaps after tumor ablation, because the combination of endarteritis and chronic ischemia caused by radiation interrupts the normal process of wound healing. These wounds will not heal spontaneously despite aggressive medical wound management. Skin grafts and local cutaneous flaps located within the radiation field are unreliable and rarely provide adequate and stable coverage. Thus, salvage surgery with a vascularized pectoralis major musculocutaneous flap is recommended as a first-line therapy for these complex wounds.

References

[1] Wei, WI; Lam, LK; Chan, VS. Current reconstruction options following tumor extirpation in head and neck surgery. Asian J Surg., 2002 Jan, 25(1), 41-8. [2] Experience with the medially based deltopectoral flap in reconstructuve surgery of the head and neck. V. Y. Bakamjian, M. Long, & B. Rigg (Eds.), Br J Plast Surg., 1971 Apr, 24(2), 174-83. [3] El-Marakby, HH. The reliability of pectoralis major myocutaneous flap in head and neck reconstruction. J Egypt Natl Canc Inst., 2006 Mar, 18(1), 41-50 [4] Schuller, DE. Cervical skin flaps in head and neck reconstruction.Am J Otolaryngol., 1981 Feb, 2(1), 62-6. [5] Triboulet, JP; Mariette, C; Chevalier, D; Amrouni, H. Factors affecting outcome in free-tissue transfer in the elderly. J. M. Serletti, J. P. Higgins, S. Moran, & G. S. Orlando (Eds.), Plast Reconstr Surg., 2000 Jul, 106(1), 66-70. Cervical Fistulae after Microsurgical Reconstruction 297

[6] Triboulet, JP; Mariette, C; Chevalier, D; Amrouni, H. Surgical management of carcinoma of the hypopharynx and cervical esophagus: analysis of 209 cases. Arch Surg., 2001 Oct, 136(10), 1164-70. [7] Coleman, JJ 3rd. Reconstruction of the pharynx and cervical esophagus. Semin Surg Oncol., 1995 May-Jun, 11(3), 208-20. [8] Bozikov, K; Arnez, ZM. J Factors predicting free flap complications in head and neck reconstruction. Plast Reconstr Aesthet Surg., 2006, 59(7), 737-42. [9] Rudolph, R. Complications of surgery for radiotherapy skin damage. Plast Reconstr Surg., 1982 Aug, 70(2), 179-85. [10] Strawberry, CW; Jacobs, JS; McCraw, JB. Reconstruction for cervical irradiation ulcers with myocutaneous flaps.Head Neck Surg., 1984 Mar-Apr, 6(4), 836-41. [11] Bakamjian, VY; Long, M; Rigg, B. Experience with the medially based deltopectoral flap in reconstructuve surgery of the head and neck. Br J Plast Surg., 1971 Apr, 24(2), 174-83. [12] Chang, YM; Coskunfirat, OK; Wei, FC; Tsai, CY; Lin, HN. Maxillary reconstruction with a fibula osteoseptocutaneous free flap and simultaneous insertion of osseointegrated dental implants.Plast Reconstr Surg., 2004, 113(4), 1140-1145. [13] Fujioka, M; Tasaki, I; Yakabe, A; Komuro, S; Tanaka, K. Reconstruction of velopharyngeal competence for composite palatomaxillary defect with a fibula osteocutaneous free flap.J Craniofac Surg., 2008 May, 19(3), 866-8. [14] Nakatsuka, T; Harii, K; Asato, H; Takushima, A; Ebihara, S; Kimata, Y; Yamada, A; Ueda, K; Ichioka, S. Analytic review of 2372 free flap transfers for head and neck reconstruction following cancer resection.J Reconstr Microsurg., 2003 Aug, 19(6), 363-8. [15] Wei, WI; Lam, LK; Chan, VS. Current reconstruction options following tumour extirpation in head and neck surgery.Asian J Surg., 2002 Jan, 25(1), 41-8. [16] Cavalot, AL; Gervasio, CF; Nazionale, G; Albera, R; Bussi, M; Staffieri, A; Ferrero, V; Cortesina, G. Pharyngocutaneous fistula as a complication of total laryngectomy: review of the literature and analysis of case records. Otolaryngol Head Neck Surg., 2000 Nov, 123(5), 587-92 [17] Markou, KD; Vlachtsis, KC; Nikolaou, AC; Petridis, DG; Kouloulas, AI; Daniilidis, IC. Incidence and predisposing factors of pharyngocutaneous fistula formation after total laryngectomy. Is there a relationship with tumor recurrence?Eur Arch Otorhinolaryngol., 2004 Feb, 261(2), 61-7. [18] Redaelli de Zinis, LO; Ferrari, L; Tomenzoli, D; Premoli, G; Parrinello, G; Nicolai, P. Postlaryngectomy pharyngocutaneous fistula: incidence, predisposing factors, and therapy. Head Neck, 1999 Mar, 21(2), 131-8. [19] Saki, N; Nikakhlagh, S; Kazemi, M. Pharyngocutaneous fistula after laryngectomy: incidence, predisposing factors, and outcome. Arch Iran Med., 2008 May, 11(3), 314-7. [20] Pinar, E; Oncel, S; Calli, C; Guclu, E; Tatar, B. Pharyngocutaneous fistula after total laryngectomy: emphasis on lymph node metastases as a new predisposing factor. J Otolaryngol Head Neck Surg., 2008 Jun, 37(3), 312-8. [21] Posner, R; Weichselbaum, RR; Fitzgerald, TJ; Clark, JR; Rose, C; Fabian, RL; Norris, CM Jr; Miller, D; Tuttle, SA; Ervin, TJ. Treatment complications after sequential 298 Masaki Fujioka

combination chemotherapy and radiotherapy with or without surgery in previously untreated squamous cell carcinoma of the head and neck.Int J Radiat Oncol Biol Phys., 1985 Nov, 11(11), 1887-93. [22] Rudolph, R; Arganese, T; Woodward, M. The ultrastructure and etiology of chronic radiotherapy damage in human skin.Ann Plast Surg., 1982 Oct, 9(4), 282-92. [23] Miller, SH; Rudolph, R. Healing in the irradiated wound. Clin Plast Surg., 1990 Jul, 17(3), 503-8. [24] Shack, RB. Management of radiation ulcers.South Med J., 1982 Dec, 75(12), 1462-6. [25] Dormand, EL; Banwell, PE; Goodacre, TE. Radiotherapy and wound healing. Int Wound J., 2005 Jun, 2(2), 112-27. [26] Mendelsohn, FA; Divino, CM; Reis, ED; Kerstein, MD. Wound care after radiation therapy. Adv Skin Wound Care, 2002 Sep-Oct, 15(5), 216-24. [27] Vartanian, JG; Carvalho, AL; Carvalho, SM; Mizobe, L; Magrin, J; Kowalski, LP. Pectoralis major and other myofascial/myocutaneous flaps in head and neck cancer reconstruction: experience with 437 cases at a single institution. Head Neck, 2004 Dec, 26(12), 1018-23. [28] Leonard, AG. Musculocutaneous flaps in head and neck reconstruction. Ann R Coll Surg Engl., 1989 May, 71(3), 159-168. In: Handbook of Pharyngeal Diseases... ISBN: 978-1-60876-430-3 Editors: A. P. Nazario, J. K. Vermeulen, pp. 299-309 © 2010 Nova Science Publishers, Inc.

Chapter XIII

Pharyngeal Dysphagia Secondary to Brain Injury (Stroke and Traumatic): Analysis of Tracheal Aspiration

Rosa Terre Unit of Functional Digestive Rehabilitation, Institut Guttmann, Badalona, Spain.

Summary

Aims

To ascertain the videofluoroscopic (VFS) pharyngeal alterations in patients with tracheal aspiration, secondary to brain injury (stroke and traumatic brain injury -TBI-) and its evolution.

Methods

Forty six patients (twenty patients with stroke and twenty-six patients with severe TBI) with videofluoroscopic diagnosis of tracheal aspiration were prospectively evaluated. Videofluoroscopic examination were performed at admission and repeated at 1, 3, 6 and 12 months of follow-up.

Results

In stroke patients at admission, we found 70% of patients with mean pharyngeal transit time (PTT) increased and pharyngeal delayed time (PDT) also in 70% of patients. In TBI we found PDT in 27% and increased PTT in 42% of patients. During follow-up, an improvement was observed in pharyngeal function, with the number of patients with aspiration decreasing, at one year aspiration persisted in 23% of stroke patients (evolution was related to the affected vascular territory: 12% of anterior territory lesions, vs 58% of posterior territory lesions), and 23% in TBI patients. At one year the mean duration of PDT and PTT in stroke patients, albeit reduced, persisted abnormally longer, 300 Rosa Terre

however in TBI patients the mean duration of these temporal measurements was normal (but 7 patients had a longer temporal measurement)

Conclusion

Swallowing physiology in stroke and in severe TBI greatly improved during follow- up and the number of aspirations decreased progressively.

Keywords: Aspiration, dysphagia, outcome, stroke, traumatic brain injury, videofluoroscopy.

Introduction

Swallowing impairments are frequent in patients during the acute phase of stroke and with severe traumatic brain injury (TBI) admitted for rehabilitation (1-5). Since food must be safely carried from the oral cavity to the stomach, many different mechanisms may affect swallowing in these patients. The swallowing process has traditionally been divided into three phases, oral, pharyngeal and esophageal, and biomechanical impairments affecting each of these phases may occur in stroke and TBI patients. Brain injuries may impair swallowing mechanisms which, in addition to cognitive and behavioral deficits which also affect the swallowing process, render both diagnosis and treatment of this condition difficult (6). Oropharyngeal dysphagia is frequently present during the acute phase of stroke and in patients with severe traumatic brain injury (TBI) admitted for rehabilitation (1-4). Reported incidence during the acute phase of stroke ranges from 22% to 70% of patients (7-11) and from 25% to 61% in TBI patients (1-4) depending on the criteria used to define dysphagia, evaluation methods and time elapsed since the brain injury, vascular territory affected in stroke and severity of the TBI. Dysphagia is more likely to occur when stroke involves the brainstem, and is present in more than half of patients with medullary strokes (12). However, it may also occur after bilateral and even unilateral cerebral hemisphere infarctions (13-16) . In these patients the reported incidence of aspiration ranged from 30% to 65% (1, 10, 12, 13). In TBI patients, the aspiration rate reported in the literature was 38-65% (2, 3, 9). Swallowing impairment is, and may be followed by pulmonary and nutritional complications (17), also dysphagia has been associated with increased morbidity and mortality following stroke (18, 19). Videofluoroscopic swallowing studies are helpful in evaluating individual pathophysiological mechanisms and their consequences in patients with oro-pharyngeal dysphagia. Schmidt et al. (20) found that the risk of developing pneumonia increased 7.6 fold in patients with videofluoroscopic evidence of aspiration compared with those without aspiration during the test. In both groups of patients fortunately, swallowing disorders improve during follow-up, so most patients with stroke dysphagia greatly improve or the disorder disappears after some days or weeks. Also, on discharge from a rehabilitation facility, 75%-94% of the total dysphagic TBI population were oral feeders (1, 21, 22). Pharyngeal Dysphagia Secondary to Brain Injury... 301

The aim of this study was to prospectively evaluate the videofluoroscopic (VFS) pharyngeal alterations in patients with tracheal aspiration, secondary to brain injury (stroke and traumatic brain injury -TBI-) and its evolution.

Patients and Method

A prospective study was conducted among 46 patients, 20 patients (9 men and 11 women) with stroke and 26 patients (20 men, 6 women) with severe TBI, Glasgow Coma Scale (GCS) 4 (range 3-8), admitted for rehabilitation treatment between June 2005 and January 2007. Mean age was 48 years (range: 19-75years) in stroke patients and 34 years (range: 16-58 years) in TBI patients and mean time elapsed from stroke-TBI to videofluoroscopic assessment was 3 months (range: 1 to 5 months). Regarding stroke etiology and location, 13 were diagnosed as hemorrhagic and 7 as ischemic, whereas 8 of lesions were located in the anterior circulation (6 belonging to the right middle cerebral artery territory and 2 to the left middle cerebral artery territory) and 12 in the posterior circulation. Mean score of the Functional Independence Measure (FIM)(23) scale was 55 (range: 15- 139). In TBI patients, outcome was evaluated with cognitive assessment using the Rancho Los Amigos Level Cognitive Function Scale (RLCF)(24), and the degree of disability with the Disability Rating Scale (DRS) (25). The RLFC consists of eight levels ranging from 1 (no response) to 8 (purposeful, appropriate). The DRS produces a quantitative index of disability across ten levels of severity, from score 30 (death) to 0 (no disability). Mean cognitive score function was 4 (range: 3-7) according to RLCF and 18 (range: 6-21) according to DRS. All TBI patients and nineteen stroke patients had a history of orotracheal intubation and tracheostomy cannulation. Follow-up was made at 1, 3, 6 and 12 months from baseline.

Videofluoroscopic Examination

The examination was carried out with boluses of 3, 5, 10 and 15 ml of pudding, nectar and liquid viscosities, with the patient seated and X-ray in the lateral projection. The full swallowing sequence was high-power recorded by the Kay Digital Swallowing Workstation (New Jersey, USA). Gastrografin® (Schering, Spain) as a contrast and Resource® as thickener are used as standard in our Unit. A complete swallowing sequence was recorded on high- resolution videotape. The VFS was an adaptation of Logemann‘s procedure (26). In the pharyngeal phase, we evaluated: 1. Nasopharyngeal penetration, which occurs as a result of inadequate velopharyngeal closure or inability of the bolus to pass through the upper esophageal sphincter (UES) causing it to ascend the nasopharyngeal tract; 2. Residue in the pharyngeal cavity after swallowing (vallecula and pyriform sinuses); 3. Cricopharyngeal dysfunction: disorders in opening of the upper esophageal sphincter, seen as defects in posterior pharynx wall relaxation; 4. Pharyngeal delay time (PDT), defined as time from bolus head arrival at the point where the shadow of the longer edge of the mandible crosses the tongue base until 302 Rosa Terre pharyngeal swallow is triggered. Triggering or onset of pharyngeal swallow is defined as the first video frame showing laryngeal elevation as part of the pharyngeal swallowing complex (considered to be normal below 0.24 sec.); 5. Pharyngeal transit time (PTT), i.e. time elapsed from when the head of the bolus goes from the base of the tongue until the tail of the bolus passes through the cricopharyngeal region (less than 1 sec. considered normal); and 6. Penetration/aspiration: penetration defined as passage of the bolus content into the laryngeal vestibule above the vocal cords. When food crossed the vocal cords and entered the airways, it was considered aspiration. Consideration was also given to the appearance or not of cough during aspiration. Silent aspiration was defined as the entry of food below the level of the true vocal cords, without cough or any outward sign of difficulty. Temporal measurements (PDT, PTT) were taken with 5ml bolus nectar.

Results

We analyzed the videofluorsocpic findings separated in relation to brain injury aetiology: stroke and TBI patients.

Stroke Patients

In the first examination, analysis of the pharyngeal phase revealed the following swallowing impairment: residue in pyriform sinus in 10%, UES impairment in 10%, PDT in 70% and increased PTT in 70%. The VFS findings are described in Table 1.

Table 1. Videofluoroscopic abnormalities at admission and during follow-up in stroke patients.

Videofluoroscopic findings Baseline 1month 3months 6months 12months % % % % % Pharyngeal residue 10 10 10 5 5 Nasopharyngeal penetration 5 0 5 0 0 Cricopharyngeal dysfunction 10 10 5 5 5 Triggering swallowing 70 55 45 35 30 reflex Increase PTT 70 50 40 30 25 Airway penetration 65 50 30 30 30 Airway aspiration 100 75 65 40 40 Silent aspiration 35 20 0 0 0 Temporal items (sec.) PDT 0.81 0.77 0.75 0.53 0.50 (≤ 0.24) (0.06-4) (0.08-4.24) (0.12-5) (0.12-3) (0.02-3) PTT 1.53 1.45 1.39 1.19 1.17 (≤ 1) (0.68-4) (0.7-5) (0.66-5 ) (0.66-4) (0.62-4) PDT: Pharyngeal delay time PTT: Pharyngeal transit time Pharyngeal Dysphagia Secondary to Brain Injury... 303

Table 2. Videofluoroscopic abnormalities and temporal measurements at baseline and during follow-up in stroke in relation to vascuar territory.

Videofluoroscopic findings AVT PVT Baseline 12 months Baseline 12 months Pharyngeal residue 12 0 8 8 Nasopharyngeal penetration 0 0 8 0 Cricopharyngeal dysfunction 12 0 8 8 PDT 62 0 75 42 Increase PTT 75 0 67 33 Airway penetration 62 25 66 33 Airway aspiration 100 12 100 58 Temporal measurements (sec.) PDT (< 0.24) 0.5 0.16 1 0.72 (0.08-1.3) (0.08-0.26) (0.12- (0.2-3) PTT (< 1) 1.25 0.84 4) 1.38 (0.7-1.9) (0.7-1) 1.7 (0.6-4) (0.7-5)

During follow-up (Table 1), an improvement in pharyngeal function was observed. Thus, at one year of follow-up, 30% had delayed PDT, and aspiration persisted in 40% of patients. When VFS findings were analyzed in relation to the vascular territory affected, some interesting differences found should be pointed out: patients with stroke in the posterior vascular territory showed more severe alteration. One third had a delay in triggering swallowing reflex; also, more severe dysfunction in swallowing physiology persisted in these patients at the end of follow-up (Table 2).

Temporal measurements of pharyngeal swallow. At baseline evaluation, mean duration of all temporal measurements (PDT and PTT) was longer than normal; the exact quantification at baseline and during follow-up are detailed in Table 1. In the analysis according to vascular territory, we found a longer mean duration of PDT and PTT at baseline in posterior territory lesions. An important difference was also found in evolution: in the anterior territory lesions, the mean duration of these temporal measurements was normal at 3 months, in contrast to the posterior territory in which at one year the mean duration of PDT and PTT measurements persisted longer (Table 3). The number of patients with aspiration on VFS examination decreased progressively during the 1-year follow-up (Table 1): 65% at 3 months and 40% at 6 months and one year. Note that the most significant change occurred at 6 months. Thirty-five percent of patients who had aspiration were silent aspirators, with no clinical or exploratory data raising the suspicion of aspiration. Also, evolution differed in relation to vascular territory. In the anterior territory lesions, patients with aspiration decreased to 37% at one month and 3 months, and at 6 months and one year aspiration persisted in only 12%. In the posterior territory lesions, more than one third had aspiration at 3 months, and the aspiration persisted in 58% at one year. 304 Rosa Terre

Table 3. Temporal videofluoroscopic measurements at baseline and during follow-up according to vascular territory.

Baseline 1month 3months 6months 12months Temporal AVT PVT AVT PVT AVT PVT AVT PVT AVT PVT measurements PDT (Mean 0.5 1 0.26 1.1 0.22 1.1 0.22 0.72 0.16 0.72 and Range) (0.06- (0.12- (0.08- (0.14- (0.14- 0.12- (0.14- (0.2- (0.14- (0.2- (normal value 1.3) 4) 0.56) 4) 060) 5) 0.60) 3) 0.26) 3) ≤ 0.24)

PTT (Mean 1.25 1.7 1 1.7 0.85 1.7 0.89 1.38 0.84 1.38 and Range) (0.7-1.9) (0.7-4) (0.7- (0.7-5) (0.7-1) 0.7-5) (0.7- (0.7- (0.7-1) (0.6- (normal value 1.5) 1.4) 4) 4) ≤ 1) PDT: Pharyngeal Delay Time PTT: Pharyngeal Transit Time AVT: Anterior vascular territory PVT: Posterior vascular territory

Table 4. Videofluoroscopic abnormalities and temporal measurements at baseline and during follow-up, in TBI patients.

Videofluoroscopic Admission 1month 3months 6months 12months findings % % % % % Pharyngeal residue 8 4 0 0 0 Nasopharyngeal 0 0 0 0 0 penetration 4 4 0 0 0 Cricopharyngeal 27 27 15 15 11 dysfunction 19 15 11 15 4 Triggering swallowing 100 65 50 31 23 reflex 35 18 0 0 0 Airway penetration Airway aspiration Silent aspiration Temporal items (sec.) PDT (Mean and 0.86 0.62 0.24 0.24 0.20 Range) ( 0.10-11.4) (0.08-8.2) (0.08-1) (0.08-1) (0.08-0.52) (normal value ≤ 0.24) 1.57 1.28 0.83 0.87 0.81 PTT (Mean and ( 0.34-12.48) (0.42-10) (0.36-1.54) (0.36-1.5) (0.36-1.36) Range) (normal value ≤ 1)

During follow-up, the number of silent aspirators also decreased: the first examination revealed 35% of patients, 27% at one month and no patients after 3 months. During follow- up, four silent aspirators in the first examination recovered cough (2 in the first month and the other 2 at three months of follow-up). Three patients who were silent aspirators at baseline continued aspirating at one year of follow-up, but recovered cough reflex during follow-up (all three cases were stroke in the posterior vascular territory).

Pharyngeal Dysphagia Secondary to Brain Injury... 305

TBI Patients

In the first examination, when the pharyngeal phase was analyzed, a residue in pyriform sinus was detected in 8%, UES impairment in 4%, PDT in 27% and increased PTT in 42% of patients. The VFS findings are described in Table 4.

During follow-up, an improvement in pharyngeal function was observed in the majority of patients (Table 3). Thus, at one year of follow-up, in relation to pharyngeal function, only 11.5% had delayed PDT.

Temporal measurements of pharyngeal swallow. At baseline evaluation, mean duration of all temporal measurements (PDT and PTT) was abnormally longer; the exact quantification and follow-up are detailed in Table 3. It is important to note that during follow-up a progressive normalization was observed in the duration of these parameters. The mean duration of these temporal measurements was normal at 3 months, and at one year only 7 patients had a longer temporal measurement. Thirty-five percent of patients who had aspiration were silent aspirators, with no clinical or exploratory data raising the suspicion of aspiration. It is of note that the number of patients with aspiration at VFS examination decreased progressively during the 1-year follow-up (Table 3): at 3 months, only half of them and at 6 and 12 months, 8 and 6, respectively. Note that the most significant change occurred at 3 months. During follow-up, the number of silent aspirators also decreased. The first examination revealed 35%, at one month 18% and after 3 months no patient had silent aspiration. During follow-up, 3 silent aspirators in the first examination recovered cough (2 in the first month and one at three months of follow-up). Only one silent aspirator in the first control continued to have aspiration at one year of follow-up, but with reflex cough.

Discussion

Swallowing impairment is common during the acute phase of stroke and after severe TBI. Published data indicates that the incidence ranges from 22% to 70% (7-11) in stroke patients and from 25% to 61% in severe TBI (1-4, 27). These variations could be due to differences in the definition of dysphagia, method of assessing swallowing function, time elapsed since the acute brain injury and the type and number of patients evaluated. In a previous report we showed oropharyngeal dysphagia to be frequent in patients not recovered from severe stroke after the acute phase, with 66% showing aspiration on videofluoroscopy (28), and in a group of patients with severe TBI and clinically-suspected dysphagia, we found a prevalence of videofluoroscopic abnormalities of 90% (with 62.5% of aspiration) (29). The studies that assessed the natural history of swallowing function after acute stroke suggested that swallowing recovers quickly; however, those studies relied on bedside clinical examination to diagnose dysphagia and only assessed swallowing function for short periods, 306 Rosa Terre such as 2 weeks after stroke (9, 30). And in TBI, some studies evaluated swallowing disorders and recovery from them with clinical assessment (21, 31) and some also with initial VFS evaluation (1, 22, 32). They reported good dysphagia evolution in many patients and 75- 94% recovered the ability to feed orally (33, 34), with impairment in the oral phase being the most prevalent dysfunction in these patients (1, 29, 31, 33, 35). In the present study, performed in patients with a videofluoroscopic diagnosis of aspiration, the main biomechanical swallowing alterations found were: delayed swallowing reflex and increase in mean PTT duration in three quarters of stroke patients and 27% in TBI patients. Most of the aspirations occurred during pharyngeal contraction, with one third of patients being silent aspirators. However, the notable part of our study was that a significant improvement was observed in swallowing physiology during follow-up, with progressive normalization of pharyngeal phase duration and a decrease in the number of laryngeal aspirations; thus, at one year 40% of stroke patients had aspiration, and less than one quarter in TBI patients. Biomechanical measurements of oropharyngeal swallow provide an objective measurement of several swallow parameters for a more precise definition of the nature of deglutition disorders and more accurate follow-up. In our study, the initial quantification and evolution differed according to the vascular territory affected in stroke patients. At baseline, PDT and PTT were longer in patients with posterior vascular lesion, and persisted abnormally longer at one year of follow-up, unlike patients with stroke in the anterior vascular territory in whom, the mean duration of all temporal measurements was within normal range at one year of follow-up. In TBI the mean duration of all temporal measurements (PDT, PTT) was longer at baseline, with all being within normal limits at one year of follow-up. Nevertheless, at one year, in 7 patients some of these temporal parameters were abnormally longer. Some studies reported a higher frequency of aspiration in patients with prolonged pharyngeal phase and also delay in initiation of the pharyngeal phase (36-38). Research on biomechanical measurements of swallowing could help clinicians to develop management and treatment plans specific to the type of swallowing problem. It should be emphasized that a reduction was also found in the number of silent aspirators during follow-up. Published data indicate that the incidence of silent aspirators ranges from 30 to 60% (10-13, 20). In our group, more than one third of the patients were silent aspirators when included in the study (with different prevalence in relation to the vascular territory affected in stroke patients), but none were at one year of follow-up; moreover, some silent aspirators recovered reflex cough during follow-up. In conclusion, the evolution of pharyngeal dysphagia in stroke patients and in severe TBI patients was towards improvement in swallowing physiology; the number of aspirations decreased progressively, with the most significant reduction observed between 3 and 6 months, with significant differences according to the vascular territory affected in stroke patients; and in TBI in the examination made at 3 months.

Pharyngeal Dysphagia Secondary to Brain Injury... 307

References

[1] Winstein, CJ. Neurogenic dysphagia. Frequency, progression, and outcome in adults following head injury. Phys Ther., 1983 Dec, 63(12), 1992-7. [2] Mackay, LE; Morgan, AS; Bernstein, BA. Swallowing disorders in severe brain injury: risk factors affecting return to oral intake. Arch Phys Med Rehabil., 1999 Apr, 80(4), 365-71. [3] Lazarus, C; Logemann, JA. Swallowing disorders in closed head trauma patients. Arch Phys Med Rehabil., 1987 Feb, 68(2), 79-84. [4] Field, LH; Weiss, CJ. Dysphagia with head injury. Brain Inj., 1989 Jan-Mar, 3(1), 19-26. [5] Teasell, RW; McRae, M; Marchuk, Y; Finestone, HM. Pneumonia associated with aspiration following stroke. Arch Phys Med Rehabil., 1996 Jul, 77(7), 707-9. [6] Logemann, J. Swallowing disorders caused by neurologic lesions from which some recovery can be anticipated. In: T. Austin, editor. Evaluation and treatment of swallowing disorders. Texax, 1998, 307-26. [7] Horner, J; Buoyer, FG; Alberts, MJ; Helms, MJ. Dysphagia following brain-stem stroke. Clinical correlates and outcome. Arch Neurol., 1991 Nov, 48(11), 1170-3. [8] Mann, G; Hankey, GJ; Cameron, D. Swallowing function after stroke: prognosis and prognostic factors at 6 months. Stroke, 1999 Apr, 30(4), 744-8. [9] Gordon, C; Hewer, RL; Wade, DT. Dysphagia in acute stroke. Br Med J (Clin Res Ed), 1987 Aug 15, 295(6595), 411-4. [10] Kidd, D; Lawson, J; Nesbitt, R; MacMahon, J. Aspiration in acute stroke: a clinical study with videofluoroscopy. Q J Med., 1993 Dec, 86(12), 825-9. [11] Daniels, SK; Brailey, K; Priestly, DH; Herrington, LR; Weisberg, LA; Foundas, AL. Aspiration in patients with acute stroke. Arch Phys Med Rehabil., 1998 Jan, 79(1), 14-9. [12] Teasell, R; Foley, N; Fisher, J; Finestone, H. The incidence, management, and complications of dysphagia in patients with medullary strokes admitted to a rehabilitation unit. Dysphagia, 2002 Spring, 17(2), 115-20. [13] Horner, J; Massey, EW; Riski, JE; Lathrop, DL; Chase, KN. Aspiration following stroke: clinical correlates and outcome. Neurology, 1988 Sep, 38(9), 1359-62. [14] Robbins, J; Levine, RL; Maser, A; Rosenbek, JC; Kempster, GB. Swallowing after unilateral stroke of the cerebral cortex. Arch Phys Med Rehabil., 1993 Dec, 74(12), 1295-300. [15] Baer, D. The natural history and functional consequences of dysphagia after hemispheric stroke. J Neurolo Neurosurg Psychiatry, 1993, 52, 236-41. [16] Wong, EH; Pullicino, PM; Benedict, R. Deep cerebral infarcts extending to the subinsular region. Stroke, 2001 Oct, 32(10), 2272-7. [17] Logemann, JA PJ; Mackay, LA. Disorders of nutrition and swallowing: intervention strategies in the trauma centre. J Head Trauma Rehabil., 1994, 9(1), 43-56. [18] ER Johnson, SM; Sievers, A. Aspiration pneumonia in stroke. Arch Phys Med Rehabil., 1993, 74(9), 973-76. 308 Rosa Terre

[19] Daniels, SK; Schroeder, MF; McClain, M; Corey, DM; Rosenbek, JC; Foundas, AL. Dysphagia in stroke: Development of a standard method to examine swallowing recovery. J Rehabil Res Dev., 2006 May-Jun, 43(3), 347-56. [20] Schmidt, J; Holas, M; Halvorson, K; Reding, M. Videofluoroscopic evidence of aspiration predicts pneumonia and death but not dehydration following stroke. Dysphagia, 1994 Winter, 9(1), 7-11. [21] Morgan, A; Ward, E; Murdoch, B. Clinical characteristics of acute dysphagia in pediatric patients following traumatic brain injury. J Head Trauma Rehabil., 2004 May-Jun, 19(3), 226-40. [22] Schurr, MJ; Ebner, KA; Maser, AL; Sperling, KB; Helgerson, RB; Harms, B. Formal swallowing evaluation and therapy after traumatic brain injury improves dysphagia outcomes. J Trauma., 1999 May, 46(5), 817-21, discussion 21-3. [23] Granger, CV; Hamilton, BB; Sherwin, FS. Guide for use of the uniform data set for medical rehabilitation. In: N. Buffalo, editor. Uniform Data System for Medical Rehabilitation, 1986. [24] Hagen, CMD; Durham, P. Levels of cognitive functioning. In Rehabilitation of the head of injured adult: Comprehensive physical management. Downey CA: Professional Staff Association of Rancho Los Amigos Hospital ed, 1999. [25] Rappaport, M; Hall, KM; Hopkins, K; Belleza, T; Cope, DN. Disability rating scale for severe head trauma: coma to community. Arch Phys Med Rehabil., 1982 Mar, 63(3), 118-23. [26] Logemann, JA. Measurement of swallow from videofluorographic studies. In: E. Pro- ed, editor. Manual for the videofluorographic study of swallowing Pro-ed, Editor Austin, Texas., 1993, 115-26. [27] Logemann, JA. Swallowing disorders caused by neurologic lesions from which some recovery can be anticipated. In: Austin Texas, editor. Evaluation and treatment of swallowing disorders. Texax, 1998, 307-26. [28] Terre, R; Mearin, F. Oropharyngeal dysphagia after the acute phase of stroke: predictors of aspiration. Neurogastroenterol Motil., 2006 Mar, 18(3), 200-5. [29] Terre, R; Mearin, F. Prospective evaluation of oro-pharyngeal dysphagia after severe traumatic brain injury. Brain Inj., 2007 Dec, 21(13), 1411-7. [30] Barer, DH. The natural history and functional consequences of dysphagia after hemispheric stroke. J Neurol Neurosurg Psychiatry., 1989 Feb, 52(2), 236-41. [31] Ward, EC; Green, K; Morton, AL. Patterns and predictors of swallowing resolution following adult traumatic brain injury. J Head Trauma Rehabil., 2007 May-Jun, 22(3), 184-91. [32] Hagen, C. Language disorders secondary to closed head injury: diagnosis and treatment. Top Lang Disord., 1981, 1, 73-87. [33] Lazarus, C. Swallowing disroders after traumatic brain injury. J Head Trauma Rehabil., 1989, 4, 34-41. [34] Mackay, LE; Chapman, PE; Morgan, AS. Maximizing Brain Injury Recovery: Integratin Critical Care and Early Rehabilitation, 1997. [35] Mackay, LE; Morgan, AS; Bernstein, BA. Factors affecting oral feeding with severe traumatic brain injury. J Head Trauma Rehabil., 1999 Oct, 14(5), 435-47. Pharyngeal Dysphagia Secondary to Brain Injury... 309

[36] Kim, Y; McCullough, GH; Asp, CW. Temporal measurements of pharyngeal swallowing in normal populations. Dysphagia, 2005, Fall, 20(4), 290-6. [37] Perlman, AL; Booth, BM; Grayhack, JP. Videofluoroscopic predictors of aspiration in patients with oropharyngeal dysphagia. Dysphagia, 1994, Spring, 9(2), 90-5. [38] McCullough, GH; Rosenbek, JC; Wertz, RT; McCoy, S; Mann, G; McCullough, K. Utility of clinical swallowing examination measures for detecting aspiration post- stroke. J Speech Lang Hear Res., 2005 Dec, 48(6), 1280-93.

Chapter XIV

Nasopharyngeal Carcinomas: What Radionuclide Imaging Can Do?

Ambreen Khawar* Pakistan Institute of Engineering and Applied Sciences, Islamabad, Pakistan.

The advent of both improved imaging systems and new radioactive agents has increased the effectiveness of nuclear medicine in diagnosing and treating various tumors. Assessment of treatment response and recurrence in the pharyngeal tumors specially the Nasopharyngeal carcinomas (NPC) has been given a considerable attention in the past decade. In this chapter, a review has been made keeping in focus, the utilization of nuclear medicine radiopharmaceutical agents like Thallium-201, Tc-99m MIBI, Tc-99m Tetrofosmin and F-18 FDG PET in the detection and evaluation of disease regression/ progression and recurrence of malignant nasopharyngeal disease. It is concluded that radionuclide imaging offers added value when compared with conventional morphological imaging techniques for the purpose of detection and evaluation of residual and recurrent Nasopharyngeal Carcinomas.

Anatomy of Nasopharynx

Nasopharynx is the superior most part of pharynx connected anteriorly to the nasal cavity bounded inferiorly by the upper aspect of the soft palate, superiorly by the base of the skull (occipital bone) and the body of the sphenoid bone. Laterally, each side contains the opening of the eustachian tube posteriorly, and a submucosal cartilaginous structure (torus tubarius), behind which is a depression (fossa of Rosenmueller) [1].

* Corresponding author: E-mail: ambreen_khawar @ hotmail.com 312 Ambreen Khawar

Nasopharyngeal Carcinoma is one of the most confusing, commonly misdiagnosed, and poorly understood diseases. In recent decades, it has attracted worldwide attention because of complex interactions of genetic, viral, environmental and dietary factors, which might be associated with the etiology of this disease.

Epidemiology

NPC has a remarkable racial and geographical distribution primarily affecting individuals from southern China and South East Asia. It has been reported to be prevalent in three widely different populations, viz. Chinese in South East Asia, Arabs in North Africa and Eskimos in the Arctic [2].The incidence of NPC is low in most part of the world (an age-adjusted incidence of less than 1 per 100,000 people). The rates are twice as high in males as in females [3, 4]. Both older people over 50 years of age and people in the second and third decades are usually affected [5]. Potential genetic determinants like H2 and BW46 and B 17 antigen have been associated with increased relative risk and increased odd ratio of disease respectively. With B 17 antigen the disease is associated with an early age of onset [6]. The association of Epstein-Barr virus and NPC was suggested by the results of sero epidemiological studies from different parts of the world and confirmed by demonstration of the persistence of EBV DNA and / or virus determined nuclear antigen (EBNA) in NPC tumor cells. In 1984 it was reported that though the role of EBV in the causation of NPC is not well understood however the viral capsid antigen IgA test allows both early detection of NPC in high incidence area and differential diagnosis in low incidence area [7]

Classification of Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma arises from the epithelium of the nasopharynx. Nearly all tumors of the nasopharynx are malignant epithelial lesions. The epithelium of the nasopharynx varies from stratified squamous to ciliated columnar. The variety of underlying epithelium results in heterogeneity of nasopharyngeal tumors. Nasopharyngeal carcinoma is subtyped into three histologic variants: keratinizing (25%), nonkeratinizing (15%), and undifferentiated (about 60%). A prominent non-neoplastic lymphoid component is frequently present, leading to the misnomer ―lymphoepithelioma.‖ [6]

Natural History of Nasopharyngeal Carcinoma

The fossa of Rosenmueller is the most common site of occurrence of nasopharyngeal carcinoma; another common area of origin is the roof of the nasopharynx. The tumor may Nasopharyngeal Carcinomas: What Radionuclide Imaging Can Do? 313 involve the mucosa or grow predominantly in the submucosa, invading adjacent tissues, including the nasal cavity. In more advanced stages the tumor may involve oropharynx, particularly the lateral or posterior wall [6] The upward extension of the tumor through basilar foramen results in cranial nerve involvement and destruction of the middle fossa. The floor of the sphenoid may occasionally be involved, showing radiographic evidence of destruction or sclerotic appearance. In approximately 5% of patients the lesion may enter into the posterior and /or medial walls of the maxillary ant rum and the ethmoids [6] The nasopharynx has a rich submucosal lymphatic network, and cervical lymph node involvement occurs early in the disease. Approximately 90% of patients develop lymphadenopathy, and it is present in 60% to 85% at the time of initial diagnosis. The incidence of distant metastasis has no relationship to the stage of the primary tumor but correlates strongly with the degree of cervical lymph node disease. The most common site of distant metastasis is bone followed closely by lung and liver [6].

Diagnosis of Nasopharyngeal Carcinoma

More than half of NPC patients present with a painless neck mass. Other presenting signs and symptoms include serous otitis media, cranial nerve involvement (the 5th and 6th are the most common), epistaxis, and nasal obstruction [8]. History and examination are the most important parts of the diagnostic evaluation. Persistent unilateral otitis media in adults should raise a strong suspicion of nasopharyngeal carcinoma. Special attention should be paid to the symptoms of unilateral nasal obstruction and/or bleeding. Flexible nasopharyngolaryngoscopy and palpation of the neck should be done if there is any suspicion of nasopharyngeal mass. Any nasopharyngeal mass or mucosal asymmetry should be biopsied. Before biopsy, however, a magnetic resonance imaging (MRI) scan of the nasopharynx and cervical region may be useful for accurate localization and extent of the mass. A computed tomography (CT) scan is the study of choice for determination of invasion of the bony base of the skull. It is preferable to obtain the radiographic studies before the biopsy in order not to mistake post biopsy changes with the lesion itself [8].

Treatment of Nasopharyngeal Carcinomas

The treatment of choice for nasopharyngeal carcinoma is high dose radiotherapy (6,500– 7,500 cGy) to the Nasopharynx and a lesser dose to the neck [9]. The response varies according to the histology of the tumor. Keratinizing tumors are not radiosensitive; however, they remain localized without dissemination. Their 5-year survival rate is 10–20%. Nonkeratinizing tumors are variably radiosensitive and have a 5-year survival rate of 35– 50%. They metastasize to regional lymph nodes. Undifferentiated tumors are radioresponsive with a 5-year survival rate of 55–65%. Radical neck dissection is indicated for persistent neck disease following radiotherapy [10]. Some surgeons have attempted resection of 314 Ambreen Khawar persistent disease in the nasopharynx, which has proved to be successful for small tumors. The role of chemotherapy is currently being studied [10]. Several factors are important in the prognosis. One is age; younger patients have a better prognosis, partly because the nasopharyngeal carcinoma occurring in younger patients is predominantly of undifferentiated type. Another factor is lymphatic metastasis. Involvement of lymph nodes decreases the overall 5-year survival by 10–20%. Other factors include clinical stage and histologic variant of the disease, as outlined above. Patients with tumors of the pharynx need close observation for the first 5 years after therapy, when they are at risk of local or regional recurrence. There is also considerable risk of developing a second primary tumor in patients who continue to smoke and drink alcohol.

Recurrent/Residual Nasopharyngeal Tumors

Accurate assessment of the status of a treated tumor is important, as early identification of recurrent tumor increases the chances of successful salvage therapy. A delay in diagnosis allows tumors to enlarge and become incurable at the time of presentation [11]. Prompt detection may permit earlier salvage of small recurrences that might be unresectable when diagnosed at a more advanced stage [12]. An imaging technique that depicts accurately early recurrences has a potential to reduce patient morbidity and mortality

Role of Conventional Radiology in Diagnosis of Recurrent/Residual Tissue

One of the most challenging issues for clinicians and radiologists is to detect recurrent tumor that has been treated previously. Surgery results in scarring and fibrosis that prevent complete evaluation of the primary site for recurrent tumor. These anatomic distortions also compromise the ability of CT and MR imaging to depict early recurrence [13]. Radiation therapy results in an inflammatory response (granulation tissue) in the tumor bed [14]. In most sites, this inflammatory response progresses to fibrosis (scarring) within 3 to 4 months after completion of radiation therapy. An inflammatory response that occurs prior to scar formation is indistinguishable from tumor by imaging [12]. The only findings diagnostic of recurrent tumor on CT or MR scans are: 1) presence of a focal mass in the location of a treated primary site; 2) lymph node metastases; 3) interval growth of a focal mass; or all three. Chemotherapy causes mucositis, erythema, and induration. Chemotherapy–associated changes also prevent thorough endoscopic evaluation and reduce the ability to detect accurately mucosal or submucosal tumor unresponsive to therapy [12, 15].

Nasopharyngeal Carcinomas: What Radionuclide Imaging Can Do? 315

Nuclear Medicine and Diagnosis of Recurrent/ Residual Nasopharyngeal Carcinoma

The role of the nuclear medicine in the diagnosis and management of malignant disease is constantly evolving. In the review of literature various studies have been found on utilization of tumor imaging radiopharmaceuticals to detect residual/recurrent tumor tissue in various carcinomas of body including pharyngeal carcinomas. Nuclear medicine techniques utilize intraveneously administered radioactive radiopharmaceuticals to obtain an image of the distribution of the radiopharmaceutical in the human body, whereas radiological techniques are based on differential absorption of radiation of an external source. Nuclear Medicine has contributed to a more functional approach in clinical oncology. As no direct relation exists between size of tumors and the number of viable malignant cells, and since metabolic alterations may precede structural alterations, metabolic tumor imaging techniques may become additional in the management of malignancies and can depict changes quite earlier than conventional imaging [16] In conventional nuclear medicine, the radionuclides which have an established role in clinical oncology are Technetium-99m (99mTc), Gallium-67 (67Ga), Thallium-201 (201Tl) and Iodine-131 (131I). In pharyngeal carcinomas the role of Tc-99m MIBI, Tetrofosmin and Thallium -201 has been explored a lot [16].

Tc-99mMIBI: is lipophilic cationic complex (Methoxy isobutyl isonitrile) empirically designed for myocardial perfusion imaging has been found useful for tumor imaging as well [16]. The cellular uptake of MIBI is related to its lipophilicity and charge. MIBI probably diffuses passively into the cell, where a strong electrostatic attraction occurs between the positive charge of the lipophilic Tc-99m MIBI molecule and the negatively charged mitochondria. Approximately 90% of Tc-99m MIBI is concentrated with in the mitochondria and hence more in a metabolically active cell [16]. The retention of Tc-99m MIBI in tumor cells is also related to its rate of transport out of the cell a cellular membrane glycoprotein, P-glycoprotein (Pgp), is responsible for pumping cationic and lipophilic substances out of the cell. This enhanced excretion mechanism is thought to be responsible for multi drug resistance (MDR) [16].

Tc-99m Tetrofosmin: is a lipophilic diphosphine routinely used for myocardial perfusion imagining and currently proposed for oncological use. The uptake is directly related to blood flow and metabolic status of the cells. It shares similar uptake mechanism and charcatersistic of extrusion by p- glycoprotein receptors of cell membrane with Tc-99m MIBI. Therefore, it can also be utilized as determinant of P-gP receptor status and hence, resistance to chemotherapy by tumor cell [16]

316 Ambreen Khawar

Thallium 201: Tl-201 chloride is a metallic element in-group IIIA of the periodic table. It decays by electron capture, emitting a cluster of x-rays ranging from 69-83 KeV (94% abundant) and two gamma rays, 167keV (10% abundant) and 135 keV (35 abundant). Physical half-life is 73 hours [16]. It is commonly thought that the primary mechanism of thallium entry into the cell is linked to the sodium/potassium adenosinetriphosphatase (ATPase) pump in the cell membrane. This system actively transports potassium into the cell in exchange for sodium, thereby creating a high intracellular potassium concentration. Biologically, thallium is thought to act similarly to potassium and competes with potassium for intracellular transport across the cell membrane via the sodium/potassium ATPase system. The reason for the elevated thallium-201 uptake in tumor has not been elucidated entirely, but is likely from the increased cellular proliferation of neoplastic cells as compared with adjacent normal tissue. Previous studies have suggested that areas of necrosis do not accumulate thallium-201 because of non-functioning of the ATPase cell membrane pump. This prevents active transport of thallium-201 into areas of necrosis. Thus, thallium-201 uptake appears to reflect the viability of the metabolic activity of tumor cells [17]. Thallium-201 single-photon emission computed tomography (thallium-201 SPECT) has gained acceptance for detecting a variety of malignant tumors. Several investigators have studied the ability of thallium-201 SPECT to depict head and neck Squamous Cell Carcinoma (HNSCCA) including pharyngeal carcinoma. Results suggest that HNSCCA is thallium-avid, and that thallium-201 SPECT accurately localizes the primary site prior to treatment as well as reveals clinically occult tumors. The degree of thallium uptake on pre-treatment imaging also may be predictive of tumor response to non surgical organ preservation therapy [17] Positron Emission Tomography (PET): is the latest development in nuclear medicine and has already established a substantial potential for applications in clinical oncology. PET differs from conventional nuclear medicine in the use of positron emitting radionuclides, and the technique allows more accurate visualization and quantification of metabolic processes in vivo. The increased utilization of glucose by metabolically active cells is the basis of increased uptake of F-18 FDG in metabolically active tumor tissue [18] This chapter aims at fostering comprehension and knowledge regarding the complexity to the issue of detection of recurrent/residual pharyngreal carcinomas with the use of both the Single photon emission computed tomography and Postron emission tomography techniques. The literature on the use of Single Photon Emitting Radionuclides: Thallium-201, Tc-99m Sestamibi, Txc-99m Tetrofosmin and F-18 FDG a positron emitter radiopharmaceutical has been reviewed incorporating the search of the MEDLINE and GOOGLE databases covering articles entered between 1989 and 2007. The sensitivities and specificities reported for Tc-99m MIBI, Tc-99m Tetrofosmin, Thallium -201 SPECT and F-18 FDG PET for detection of recurrent / residual nasopharyngeal carcinoma have been compared. The means of to both the sensitivities and specificities of these modalities are obtained and t test applied and p<0.05 is considered to be significant. The analysis of sensitivities and specificities of a total of eight studies performed on 173 patients [19-25] for detection of residual/recurrent nasopharyngeal carcinomas in which comparison of Tc-99m MIBI and CT/MRI was done is given in the Figure 1.1. The Nasopharyngeal Carcinomas: What Radionuclide Imaging Can Do? 317 comparison of means of sensitivities and specificities of Tc-99m MIBI and CT/MRI by t-test also confirmed that the difference in the means of sensitivities of two was non significant (p>0.05) while the difference between means of specificities was significant (p<0.05) i.e. the Tc-99m MIBI SPECT was proved to be more specific than CT/MRI in the detection of residual/recurrent nasopharyngeal carcinoma. The comparison of Tc-99m Tetrofosmin and CT/MRI in 4 studies [21,26-28,] incorporating 114 patients for recurrent/residual nasopharyngeal carcinomas revealed that both share same sensitivity but the specificity of Tc-99m Tetrofosmin remained better than CT/MRI. However due to less number of studies available the t- test did not revealed any significant difference between the radionuclidic and conventional imaging modalities (p>0.05). The comparison of sensitivity and specificity between Thallium 201 and CT/MRI in studies [19, 20, 25, 29, 30, 31] conducted in 145 patients revealed the high specificity and almost equal sensitivity in three studies and even in the cases where the CT/ MRI remained indeterminate the Thallium -201 scan proved to be an excellent tool to detect recurrent/residual nasopharyngeal tumor tissue and resulted in high sensitivity and specificity (80%-95%) as shown in Figure 3.

120 100 TC-99m MIBI Sensitivity 80 CT/MRI sensitivity 60 40 Tc-99m MIBI Specificity 20 CT/MRI Specificity 0 1 2 3 4 5 6 7 8

Figure 1: Comparison of Sensitivity/ Specificity between Tc-99m MIBI and CT/MRI.

120 100 Tc-99m Tetrofosmine 80 Sensitivity CT/MRI Sensitivity % % 60 40 20 Tc-99m Tetrofosmine Specificity 0

Sensitivity/Specificity CT/MRI Specificity 1 2 3 4 Number of Studies

Figure 2: Comparison of Sensitivity/ Specificity between Tc-99m Tetrofosmin and CT/MRI 318 Ambreen Khawar

120 Thallium- 201 100 Sensitivity 80 CT/MRI Sensitivity % % 60 40 20 Thallium 0 Specificity Sensitivity/Specificity 1 2 3 4 5 6 7 CT/MRI Specificity Number of Studies

Figure 3: Comparison of Sensitivity and Specificity between Thallium 201 and CT/MRI.

120 F-18 FDG 100 Sensitivity 80 60 CT/MRI Sensitivity 40

Specificity F-18 FDG

% Sensitivity/ 20 0 Specificity 1 2 3 4 5 6 CT/MRI Specificity Number of Studies

Figure 4: Comparison of Sensitivity and Specificity between F-18 FDG and CT/MRI.

120.0 100.0 CT/MRI 80.0 Tc-99m MIBI 60.0 Tc-99m Tetrofosmine 40.0 Thallium -201 F-18 FDG 20.0

and Specificities (2) 0.0 Means of Sensitivities(1) 1 2 Types of Studies

Figure 5: Comparison of mean sensitivity/specificity of different imaging modalities

The sensitivity and specificity of F-18 FDG for recurrent/ residual nasopharyngeal tumor detection reported in six studies [22, 27, 30, 32, 33, and 34] conducted in 202 patients remained high as compared to CT/ MRI as shown in Figure 4. The comparison of means of sensitivities and specificities of all radionuclidic (SPECT and PET) studies with CT/MRI in Figure 5 also support the higher specific diagnostic ability of radionuclidic imaging than conventional modalities. Among the radionuclidic studies F-18 Nasopharyngeal Carcinomas: What Radionuclide Imaging Can Do? 319

FDG metabolic imaging has the highest sensitivity and specificity for NPC. In comparison of the SPECT radiopharmaceuticals the Thallium-201 has high sensitivity as compared to Tc- 99m MIBI and Tc-99m Tetrofosmin but it shares less specificity as compared to Tc-99m labeled MIBI and Tetrofosmin. However the highest specificity almost comparable to F-18 FDG but is less sensitive than Thallium-201 and Tc-99m MIBI both. However if the prospects of utilization of Tc-99m MIBI are seen than it seems quite a suitable single photon emitting radiopharmaceutical as it has got a reasonable sensitivity and specificity both.

Conclusions

The review of all the studies suggests F-18 FDG positron emission tomography the best modality for detection of residual and recurrent nasopharyngeal carcinoma. However in the absence of PET facitities, Tc-99m MIBI is quite an appropriate single photon emitting agent which should be utilized for pre and post therapy studies be it be surgery, radio or chemotherapy for detection of residual or recurrent disease.

References

[1] Snell, R. S. (1992). Clinical Anatomy for Medical Students, 4th edition. Boston: Little, Brown and Company, 863-870. [2] The, G. (1982). Epidemiology of the Epstein Barr virus and associated disease. In: Herpes Viruses. B. Riozman, (Ed.), Plenum Press, New York, (Vol. A 1), 460. [3] Hirayama, T. (1978). Descriptive and analytical epidemiology of Nasopharyngeal cancer. In: Nasopharyngeal Carcinoma: Etiology and Control. G. de The, & Y, Ito (Eds.), IARC Scientific Pub, 20, 167. [4] Ho, J. H. (1976). Epidemiology of nasopharyngeal carcinoma. In: Cancer in Asia. T. Hirayama. (Eds.), Baltimore University Press, 49. [5] Kumar, S., Zinyu, R., Singh, I. K. K., Medhi, S. B., Baruah, T., Das, B. & Dutta, L. P. (1996). Studies on nasopharyngeal carcinoma with reference to the North Eastern Region of India. Ann Natl Acad Med Sci (India), 32, 199. [6] Schantz, S. P., Harrison, L. B. & Forastiere, A. A. (2001). Tumors of the Nasal Cavity and Paranasal Sinuses, Nasopharynx, Oral Cavity and Oropharynx. In: Cancer Principles and Practice of Oncology, 6th edition Part I. Philadelphia: Lippincott Williams and Wilkins, 797-850. [7] Lavine, P. H., Conelly, R. R., Nilman, G. & Easten, J. (1998). Epstein Barr virus serology in the control of nasopharyngeal carcinoma. Cancer Detect Prev, 12, 357. [8] Perez, C. A. (1998). Nasopharynx. In: Principles and Practice of Radiation Oncology, 3rd edition Volume. Philadelphia:Lippincott- Raven, 897-940. [9] Le, Q. T., Tate, D., Koong, A., et al. (2003). Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma: In. J Radiat Oncol Biol Phys, 56(4), 1046-1054. [10] Al-Sarraf, M. & McLaughlin, P. W. (1995). Nasopharynx carcinoma: choice of treatment. In J Radiat Oncol Biol Phys, 33, 761-763. 320 Ambreen Khawar

[11] Anzai, Y., Carroll, W. R., Quint, D. J., et al. (1996). Recurrence of head and neck cancer after surgery or irradiation: prospective comparison of 2-deoxy-2-[F-18] fluoro- D-glucose PET and MR imaging diagnoses. Radiology, 200, 135-141. [12] Bronstein, A. D., Nyberg Schwartz, A. N., Shuman, W. P. & Griffen, B. R. (1989). Soft tissue changes after head and neck radiation: CT findings. Am J Neuroradiol, 10, 171-175. [13] Hudgins, P. A., Burson, J. G., Gussack, G. S. & Grist, W. J. (1994). CT and MR appearance of recurrent malignant head and neck neoplasms after resection and flap reconstruction. Am J Neuroradiol, 15, 1689-1694. [14] Manara, M. (1966). Histologic changes of the human larynx irradiated with various technical therapeutic methods. Arch Ital Otolaryngol, 78, 596-635 [15] Glazer, H. S., Niemeyer, J. H., Balfe, N. M., et al. (1986). Neck neoplasms: MR Imaging in Post treatment evaluation. Radiology, 160, 349-354. [16] Thrall, J. H. & Ziessman, H. A. (2001). Oncology, In. J. H. Thrall, & H. A. Ziessman (Eds.), Nuclear Medicine The Requisites, second edition. St Louis, Missouri, 193-227. [17] Valdes Olmos, R. A., Balm, A. J. M., Hilgers, F. J. M., et al. (1997). Tl-201 SPECT in the diagnosis of head and neck cancer. J Nucl Med, 38, 873-879. [18] Kuni, C. C. & duCret, R. P. (1997). Radiopharmaceuticals used in Scintigraphy: In. C. C. Kuni, & R. P. duCret (Eds.), Manual of Nuclear Medicine Imaging. Thiene Medical Publishers, New York, 267-273. [19] Kostakoglu, L., Uysal, U., Ozyar, E., et al. (1996). Pre- and Post- therapy Thalium -201 and Technitium -99m –Sestamibi SPECT in Nasopharyngeal Carcinoma. J Nucl Med, 37, 1956-1962. [20] Kostakoglu, L., Uysal, U., Ozyar, E., et al. (1997). Monitoring Response to Therapy with Thallium- 201 and Technitium- 99m- Sestamibi SPECT in Nasopharyngeal Carcinoma. J Nucl Med, 38, 1009-1014. [21] Kostakoglu, L., Uysal, U., Ozyar, E., et al. (1997). A Comparative Study of Technitium- 88m Sestamibi and Technitium-99m Tetrofosmin Single Photon Tomography in the Detection of Nasopharyngeal Carcinoma. Eur J Nucl Med, 24, 621-628. [22] Kao, C. H., Shiau, Y. C., et al. (2002). Detection of Recurrent or Persistent nasopharyngeal Carcinomas after Radiotherapy with Technitium – 99m Methoxy isobutylisonitrile Single Photon emission Computed Tomography and Computed Tomography Comparison with 18- Fluoro- 2 Deoxyglucose Positron Emission Tomography. Cancer, 94(7), 1981-1986. [23] Shiau, Y. C., Tsai, S. C., Ho, Y. J. & Kao, C. H. (2001). Comparison of technetium- 99m methoxy isobutyl isonitrile single photon emission computed tomography and computed tomography to detect recurrent or residual nasopharyngeal carcinomas after radiotherapy. Anticancer Res, 21(3C), 2213-7. [24] Pui, M. H., Du, J. Q., Yueh, T. C. & Zeng, S. Q. (1998). Imaging of nasopharyngeal carcinoma with Tc-99m MIBI. Clin Nucl Med, 23(1), 29-32. [25] Sobic Saranovic., et al. (2007). Evaluation of Undifferentiated Carcinoma of Nasopharyngeal Type with Thallium- 201 and Technitium -99m MIBI SPECT. Otolaryngology–Head and Neck Surgery, 137, 405-411. Nasopharyngeal Carcinomas: What Radionuclide Imaging Can Do? 321

[26] Tai, C. J., Shiau, Y. C., Wang, J. J., et al. (2003). Detection of recurrent or residual nasopharyngeal carcinomas after radiotherapy with technetium-99m tetrofosmin single photon emission computed tomography and comparison with computed tomography--a preliminary study. Cancer Invest, 21(4), 536-41. [27] Kao, C. H., Tsai, S. C., et al. (2001). Comparing 18-fluoro-2-deoxyglucose positron emission tomography with a combination of technetium 99m tetrofosmin single photon emission computed tomography and computed tomography to detect recurrent or persistent nasopharyngeal carcinomas after radiotherapy. Cancer, 92(2), 434-439. [28] Yih, C. Weng, Ruoh, F., et al. (2003). Detection of Recurrent Nasopharyngeal Carcinomas After Radiotherapy with Technetium-99m Tetrofosmin Single Photon Emission Computed Tomography in Patients with Indeterminate Magnetic Resonance Imaging Findings. Cancer Investigation, 21(5), 695-700. [29] Shiau, Y. C., Liu, F. Y., et al. (2003). Using Thallium-201 SPECT To Detect Recurrent Or Residual Nasopharyngeal Carcinoma After Radiotherapy in Patients with Indeterminate CT Findings, Head and Neck, 645-648. [30] Tsai, M. H., Huang, W. S., et al. (2003). Differentiating Recurrent or Residual Nasopharyngeal Carcinomas from Post- radiotherapy Changes with 18-Fluoro- 2 Deoxyglucose Positron Emission Tomography and Thallium- 201 Single Photon Emission computed Tomography in Patients with indeterminate Computed Tomography Findings. Anticancer Research, 23, 3513-3516. [31] Tai, C. J., et al. (2002). Detection of recurrent nasopharyngeal carcinomas with thallium-201 single-photon emission computed tomography in patients with indeterminate magnetic resonance imaging findings after radiotherapy. Head and Neck, 25(3), 227-231. [32] Tsai, M. H., Shiau, Y. C., Kao, C. H., et al. (2002). Detection of Recurrent Nasopharyngeal Carcinomas with Positron Emission Tomography Using 18-Fluoro-2- Deoxyglucose in Patients with Indeterminate Magnetic Resonance Imaging Findings after Radiotherapy. J Cancer Res Clin Oncol, 128, 279-282. [33] Kao, C. H., ChangLai, S. P., Chieng, P. U., Yen, R. F. & Yen, T. C. (1998). Detection of recurrent or persistent nasopharyngeal carcinomas after radiotherapy with 18-fluoro- 2-deoxyglucose positron emission tomography and comparison with computed tomography. Journal of Clinical Oncology, 16, 3550-3555. [34] Peng, N., Yen, S., Liu, W., Tsay, D. & Liu, R. (2000). Evaluation of the Effect of Radiation Therapy to Nasopharyngeal Carcinoma by Positron Emission Tomography with 2-[F-18]fluoro-2-deoxy-D-glucose (PET-FDG). Clin Positron Imaging, 3(2), 51-56.

Chapter XV

Reconstructive Options for Free Radial Forearm Flap Donor Defect in Pharyngeal and Laryngeal Reconstruction

Kao-Ping Chang1,2 and Chung-Sheng Lai1,2 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 2 Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Abstract

There are studies contributing alternatives to restoring the donor site of free radial forearm flap (FRFF) , indicated for reconstruction of pharyngeal and laryngeal defects, other than split thickness skin graft, such as: full thickness skin grafts, artificial dermis (Alloderm), and negative pressure wound dressing. These techniques are all aimed at establishing thin layer skin coverage. A local bilobed flap, playing a role as a second flap, is applied to cover FRFF donor site and offered as a similar soft tissue. However, the hard scar texture and secondary contracture of the skin graft cause unfavorable sequelae in hand movement and cosmetic results. Limitation of flap size and necrosis of local flaps are often occurred. To simultaneously overcome the important drawback of sacrificing the radial artery in cases of FRFF, we reported our method for restoration of radial artery in the use of anterolateral thigh (ALT) flap. The FRFF donor site is repaired in our series by the ALT, a second fasciocutaneous flap. The latter offers great and similar soft tissue coverage, which, unlike skin grafts, does not result in contracture. Also, there is neither the risk of tendon exposure nor flexor contracture. All major donor site morbidities of the FRFF were solved by the ALT flap coverage, except for abnormal sensations of the radial side of the donor hand. Therefore, the FRFF is a proper choice for pharyngeal and laryngeal defects. When it is chosen for its unique merits, the ALT flap can also serve as an alternative in reconstructing the donor site with least morbidity.

324 Kao-Ping Chang, Chung-Sheng Lai and Ching-Hung Lai

Introduction

Free radial forearm flap (FRFF) has replaced the pedicled pectoralis myocutaneous flap and become the ―workhorse flap‖ used for head and neck reconstruction. It is also an appropriate choice for smaller tongue defects [1]. Although ALT flap has been reported as a substitute for FRFF in similar types of reconstruction [2-4], the FRFF still has some undeniable merits, including thinness, reliable vasculature, relatively short harvesting time and ease of dissection. These characteristics make the FRFF a perfect fasciocutaneous flap for defects located in more dynamic and uneven surfaces, especially when the flap is taken to fit in a small and winding contour, where flap folding is needed [1, 3]. Despite the skin graft is the method of choice for traditional FRFF donor site resurfacing, the morbidities of the FRFF donor sites have been widely discussed [5]. These morbidities are mainly due to loss of the skin graft over the tendons. Flexor carpi radialis tendon exposure and adhesion formation cause delayed healing, poor appearance, and functional restrictions [6]. Although ALT flap is widely applied and one of its primary advantages is the minimal donor-site morbidity [4], ALT flap can also be an excellent alternative to skin graft for FRFF donor site reconstruction. Therefore, in this review of reconstructive options for FRFF donor defect, we proposed an alternative reconstructive method of simultaneously using the ALT flap to reconstruct the FRFF donor defect to minimize the morbidities of skin graft and radial artery incompetence.

Optimal Flap for Head and Neck Reconstruction

There is no real ―indication‖ for a specific flap, and all flaps have their own advantages and disadvantages. The choice of flap seems dependent on the surgeon‘s training and experience. However, there are certain indications for flaps used in head and neck reconstructions as Lyons stated [7]. (a) The tissue harvested should be pliable so as not to impair movement and function in its new position in the head and neck. (b) The pedicle should be long, large and consistent. (c) The flap must be reliable. (d) Small and large flaps with variable thicknesses should be possible. (e) Raising the flap should be simple. (f) Raising the flap should be possible in the supine position, to permit synchronous harvest during head and neck surgery. (g) The donor site morbidity should be low, both in terms of function and cosmetics. (h) There should be nerves available in the area whose harvest should not cause morbidities. The FRFF fits all these criteria and is, without a doubt, a popular flap for tongue reconstruction [7, 8]. Since its introduction in 1981 by Yang et al. [9, 10], the FRFF has gained increasing popularity in head and neck reconstruction, based on its abundant supply of thin, pliable, sensate skin and its long, reliable pedicle. Therefore, the harvest of FRFF results in relatively more reliable circulation compared to ordinary perforator flaps. When thinner flaps are used to mimic the shape of the tongue, and folded to fit the curvature of the mouth floor, a strong and reliable vascular structure is preferred to avoid circulation compromise, especially when flap folding is inevitable. Our experience is to

Reconstructive Options for Free Radial Forearm Flap Donor... 325 provide an alternative option for the donor defect of FRFF, especially when radial forearm flap is comparatively preferred than ALT flap in certain head and neck reconstruction.

Preoperative Assessment of Adequate Hand Perfusion by Unlar Artery Only in Patietns with the Subjective Allen’s Test

The blood supply to the hand depends on the radial and ulnar arteries. The radial artery enters the hand and forms the deep palmar arch after giving rise to the princeps pollicis and radialis indicis arteries. The ulnar artery enters to the hand to form the superficial palmar arch. The communication between the radial and unlar arteries is complete in 35% of the dual system, with 21% of incomplete superficial arch and 3% of incomplete deep arch [11]. Although overall success rates of 97% of good radio-unlar communication have been reported [12]. However, these excellent results depend partly on the good candidate of donor site selection, which has generally been based on adequate unlar artery perfusion to supply the whole hand, as tested by Allen‘s test [13, 14]. Allen‘s test is originally described by Allen in 19291 [15] and has been the standard method of evaluating the circulation of the hand. There exist 2-20% of hands with an absence of collateral flow [16, 17]. Furthermore, blood flow of the radial artery was not rebuilt in traditional harvesting of the FRFF, although blood perfusion in the hand is not impaired [18-20]. However, the change of forearm vasculature after losing the radial artery has been reported [21], and cold intolerance has been reported for up to 26.7~31.4% of all patients.[22-24].

Options for Resurfacing the Donor Defect of Radial Forearm Flap and Their Pitfall and Complication

There is controversy in the literature regarding donor site morbidity following radial forearm flap harvesting. Studies therefore have been focusing on the aesthetics and functional impairment of the donor site. Most of the morbidities are about poor appearance (2~8%), delayed wound healing with partial skin graft failure (2~53%), tendon exposure (0~33%), scar contracture (11.4%), sensory impairment of the donor hand (17~54%), and cold intolerance (~26.7%) [6, 25]. There are studies contributing alternatives to restoring the FRFF donor site other than split thickness skin graft, such as: full thickness skin grafts [26], artificial dermis (Alloderm) [27], and negative pressure wound dressing [28]. These techniques are all aimed at establishing thin layer skin coverage. However, the hard scar texture and secondary contracture of the skin graft cause unfavorable sequelae in hand movement and cosmetic results. These complications could be eliminated once a

1 Allen EV. Thromboangitis obliterans: methods of diagnosis of chronic occlusive arterial lesion distal to the wrist with illustrative cases. Am J Med Sci 1929;178:237-44. 326 Kao-Ping Chang, Chung-Sheng Lai and Ching-Hung Lai fasciocutaneous flap is used as the choice of donor site reconstruction. A local bilobed flap, playing a role as a second flap, is applied to cover FRFF donor site and offered as a similar soft tissue. However, there are still pitfalls, such as limitation of flap size and necrosis [29]. The FRFF donor site, serving as a defect caused by the first lobe, is repaired in our series by the ALT, a second fasciocutaneous flap. The latter offers great and similar soft tissue coverage, which, unlike skin grafts, dose not result in contracture. Also, there is neither the risk of tendon exposure nor flexor contracture.

Conventional Split-Thickness Skin Graft

Split-thickness skin graft (STSG) has been the most commonly used method of reconstruction due to its ease in harvesting and use. However, a number of associated morbidities, such as partial skin graft loss and flexor tendon exposure, have been reported.

Full-Thickness Skin Graft

A full thickness skin graft (FTSG) is usually harvested from the groin area. The use of FTSG was previously described by Sleeman et al. [30] and followingly by some other groups [31, 32] where the authors reported improved wound healing, decreased rate of wound breakdown, and better aesthetic results than with that of STSG.

Artifial Dermis

Artifial dermis (Alloderm) has been used successfully in a variety of situations, including in burn reconstructions [33], filling soft tissue defects [34], and cosmetic surgery [35, 36]. Rowe et al. [37] reported that composite grafting with Alloderm and STSG provides a comparable result with traditional STSG for the treatment of radial forearm graft donor site.

Negative Pressure Device

Greer et al. have previously described the use of the vacuum-assisted closure (negative pressure device) system to treat exposed tendons over the radial forearm donor site [38]. They reported to place the vacuum-assisted system to promote granulation tissue growth over tendons. Andrew et al. [39] applied the same experience in patients with compromised skin graft healing. The negative pressure device system was left in place until a healthy granulation tissue bed was prepared over the exposed tendons and then the wound was left to be secondary healing or to be grafted. Therefore, negative pressure device system might improve wound healing time, simplified wound care, and eliminated the need for further procedures.

Reconstructive Options for Free Radial Forearm Flap Donor... 327

Local Flap

Local flaps based on the radial or ulnar artery perforators for distal forearm reconstruction have been successfully used, with quite large flaps being supplied by even a single perforator [40, 41]. Hsieh et al. described bilobed flap based on the fasciocutaneous perforator of the ulnar artery to close primarily the donor site of radial forearm flap [29].

Secondary Free Flap

The ALT flap is the perforator flap which may currently be the main rival of FRFF for reconstructing head and neck defects. However, the ALT flap might be too ―plump‖ or thick when applied to a relatively small intraoral or tongue defect, especially in Western populations, which usually have thicker layers of subcutaneous fat than Asians. Dealing with potentially hairy flap skin in the mouth is also a troublesome problem [3]. The concept of one-stage thinning has been described with regard to perforator flaps in Asia [42, 43], but despite the fact that success rate of flap thinning is high in some studies [44], the result of flap thinning technique has not met with favor in Caucasian populations [22]. The perforator morphology of the ALT flap varies from type to type [45]. Although the ALT flap may present a bulky appearance rather than the thickened contracture scar of a skin graft, the color of the flap is usually similar to the forearm skin and there is little or no adhesion to the flexor tendon underneath. A secondary revision can be arranged to flatten the elevated flap mass by liposuction [46] and the final appearance of the donor arm would have only round and curved incision scar remaining. On the other hand, circulation of the radial artery, which is supposed to be sacrificed after raising the FRFF, is rebuilt by the flow-through pedicle of the ALT flap in our study. Under these circumstances, cold intolerance induced by insufficient radial circulation has never been recorded in our study. There are still some disadvantages to our double flaps method, such as time-consuming, manpower-demanding, longer hospitalization, and sensory impairment.

Conclusion

Many techniques have been developed to reconstruct donor sites of free radial forearm flaps to achieve good cosmetic outcome and to eliminate morbidities. The main problems of the donor site are delayed healing, motor or sensory impairment, and poor aesthetic appearance. Undoubtedly, the free radial forearm flap is a better choice for small and winding contours in certain indications. In these circumstances, ALT flaps can be used as an alternative for repairing the forearm donor site, and morbidities caused by the sacrifice of a great vessel, sensory impairment and graft contracture can be prevented by this method. Greater demand for manpower is the main issue, otherwise ALT flap coverage for FRFF donor sites is ideal for eliminating morbidities caused by the traditional method, as long as the patients‘ benefits could be more preserved. 328 Kao-Ping Chang, Chung-Sheng Lai and Ching-Hung Lai

Referenes

[1] Hsiao, H. T., Leu, Y. S. & Lin, C. C. (2002). Primary closure versus radial forearm flap reconstruction after hemiglossectomy: functional assessment of swallowing and speech. Ann Plast Surg, 49(6), 612-6. [2] Chen, C. M., et al. (2005). Anterolateral thigh flaps for reconstruction of head and neck defects. J Oral Maxillofac Surg, 63(7), 948-52. [3] Hurvitz, K. A., Kobayashi, M. & Evans, G. R. (2006). Current options in head and neck reconstruction. Plast Reconstr Surg, 118(5), 122e-133e. [4] Wei, F. C., et al. (2002). Have we found an ideal soft-tissue flap? An experience with 672 anterolateral thigh flaps. Plast Reconstr Surg, 109(7), 2219-26; discussion 2227- 30. [5] Lutz, B. S., et al. (1999). Donor site morbidity after suprafascial elevation of the radial forearm flap: a prospective study in 95 consecutive cases. Plast Reconstr Surg, 103(1), 132-7. [6] Chen, C. M., et al. (2005). Complications of free radial forearm flap transfers for head and neck reconstruction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 99(6), 671-6. [7] Lyons, A. J. (2006). Perforator flaps in head and neck surgery. Int J Oral Maxillofac Surg, 35(3), 199-207. [8] O'Brien, C. J., et al. (1998). Evaluation of 250 free-flap reconstructions after resection of tumours of the head and neck. Aust N Z J Surg, 68(10), 698-701. [9] Yang, G. F., et al. (1997). Forearm free skin flap transplantation: a report of 56 cases. 1981. Br J Plast Surg, 50(3), 162-5. [10] Germain, M. A., et al. (1991). [Free forearm flap used in the reconstruction of the cervico-cephalic region. 43 cases]. Chirurgie, 117(3), 236-43. [11] Nuckols, D. A., et al. (2000). Preoperative evaluation of the radial forearm free flap patient with the objective Allen's test. Otolaryngol Head Neck Surg, 123(5), 553-7. [12] Evans, G. R., et al. (1994). The radial forearm free flap for head and neck reconstruction: a review. Am J Surg, 168(5), 446-50. [13] Song, R., et al. (1982). The forearm flap. Clin Plast Surg, 9(1), 21-6. [14] Chang, Y. L. & Mahoney, J. L. (1990). A forearm free flap based on an occluded radial artery: its salvage and avoidance. Ann Plast Surg, 24(5), 455-8. [15] Allen, E. V. (1929). Thromboangitis obliterans: methods of diagnosis of chronic occlusive arterial lesion distal to the wrist with illustrative cases. Am J Med Sci, 178, 237-44. [16] Doscher, W., et al. (1985). Physiologic anatomy of the palmar circulation in 200 normal hands. J Cardiovasc Surg (Torino), 26(2), 171-4. [17] Husum, B. & Berthelsen, P. (1981). Allen's test and systolic arterial pressure in the thumb. Br J Anaesth, 53(6), 635-7. [18] Bardsley, A. F., et al. (1990). Reducing morbidity in the radial forearm flap donor site. Plast Reconstr Surg, 86(2), 287-92; discussion 293-4. [19] Boorman, J. G., Brown, J. A. & Sykes, P. J. (1987). Morbidity in the forearm flap donor arm. Br J Plast Surg, 40(2), 207-12.

Reconstructive Options for Free Radial Forearm Flap Donor... 329

[20] Bootz, F. & Biesinger, E. (1991). Reduction of complication rate at radial forearm flap donor sites. ORL J Otorhinolaryngol Relat Spec, 53(3), 160-4. [21] Ciria-Llorens, G., Gomez-Cia, T. & Talegon-Melendez, A. (1999). Analysis of flow changes in forearm arteries after raising the radial forearm flap: a prospective study using colour duplex imaging. Br J Plast Surg, 52(6), 440-4. [22] Alkureishi, L. W., Shaw-Dunn, J. & Ross, G. L. (2003). Effects of thinning the anterolateral thigh flap on the blood supply to the skin. Br J Plast Surg, 56(4), 401-8. [23] Swanson, E., Boyd, J. B. & Manktelow, R. T. (1990). The radial forearm flap: reconstructive applications and donor-site defects in 35 consecutive patients. Plast Reconstr Surg, 85(2), 258-66. [24] Timmons, M. J., et al. (1986). Complications of radial forearm flap donor sites. Br J Plast Surg, 39(2), 176-8. [25] Toschka, H., et al. (2001). Aesthetic and functional results of harvesting radial forearm flap, especially with regard to hand function. Int J Oral Maxillofac Surg, 30(1), 42-8. [26] Gaukroger, M. C., et al. (1994). Repair of the radial forearm flap donor site with a full- thickness graft. Int J Oral Maxillofac Surg, 23(4), 205-8. [27] Lee, J. W., Jang, Y. C. & Oh, S. J. (2005). Use of the artificial dermis for free radial forearm flap donor site. Ann Plast Surg, 55(5), 500-2. [28] Avery, C., et al. (2000). Negative pressure wound dressing of the radial forearm donor site. Int J Oral Maxillofac Surg, 29(3), 198-200. [29] Hsieh, C. H., et al. (2004). Primary closure of radial forearm flap donor defects with a bilobed flap based on the fasciocutaneous perforator of the ulnar artery. Plast Reconstr Surg, 113(5), 1355-60. [30] Sleeman, D., Carton, A. T. & Stassen, L. F. (1994). Closure of radial forearm free flap defect using full-thickness skin from the anterior abdominal wall. Br J Oral Maxillofac Surg, 32(1), 54-5. [31] Sidebottom, A. J., et al. (2000). Repair of the radial free flap donor site with full or partial thickness skin grafts. A prospective randomised controlled trial. Int J Oral Maxillofac Surg, 29(3), 194-7. [32] van der Lei, B., Spronk, C. A. & de Visscher, J. G. (1999). Closure of radial forearm free flap donor site with local full-thickness skin graft. Br J Oral Maxillofac Surg, 37(2), 119-22. [33] Wainwright, D. J. (1995). Use of an acellular allograft dermal matrix (AlloDerm) in the management of full-thickness burns. Burns, 21(4), 243-8. [34] Achauer, B. M., et al. (1998). Augmentation of facial soft-tissue defects with Alloderm dermal graft. Ann Plast Surg, 41(5), 503-7. [35] Gryskiewicz, J. M., Rohrich, R. J. & Reagan, B. J. (2001). The use of alloderm for the correction of nasal contour deformities. Plast Reconstr Surg, 107(2), 561-70; discussion 571. [36] Tobin, H. A. & Karas, N. D. (1998). Lip augmentation using an alloderm graft. J Oral Maxillofac Surg, 56(6), 722-7. [37] Rowe, N. M., Morris, L. & Delacure, M. D. (2006). Acellular dermal composite allografts for reconstruction of the radial forearm donor site. Ann Plast Surg, 57(3), 305-11. 330 Kao-Ping Chang, Chung-Sheng Lai and Ching-Hung Lai

[38] Greer, S. E., et al. (1999). The use of subatmospheric pressure dressing for the coverage of radial forearm free flap donor-site exposed tendon complications. Ann Plast Surg, 43(5), 551-4. [39] Andrews, B. T., et al. (2006). Management of the radial forearm free flap donor site with the vacuum-assisted closure (VAC) system. Laryngoscope, 116(10), 1918-22. [40] Jeng, S. F. & Wei, F. C. (1998). The distally based forearm island flap in hand reconstruction. Plast Reconstr Surg, 102(2), 400-6. [41] Yii, N. W. & Niranjan, N. S. (1999). Fascial flaps based on perforators for reconstruction of defects in the distal forearm. Br J Plast Surg, 52(7), 534-40. [42] Kimura, N. & Satoh, K. (1996). Consideration of a thin flap as an entity and clinical applications of the thin anterolateral thigh flap. Plast Reconstr Surg, 97(5), 985-92. [43] Kimura, N., et al. (2001). Clinical application of the free thin anterolateral thigh flap in 31 consecutive patients. Plast Reconstr Surg, 108(5), 1197-208; discussion 1209-10. [44] Kimura, N., et al. (2006). Giant combined microdissected thin thigh perforator flap. J Plast Reconstr Aesthet Surg, 59(12), 1325-9. [45] Richardson, D., et al. (1997). Radial forearm flap donor-site complications and morbidity: a prospective study. Plast Reconstr Surg, 99(1), 109-15. [46] Mowlavi, A. & Brown, R. E. (2003). Suction lipectomy during flap reconstruction provides immediate and safe debulking of the skin island. Ann Plast Surg, 51(2), 189-93.

Chapter XVI

Distribution of Tumor Necrosis Factor Producing Cells in Chronic Tonsillitis

1Milan Stankovic*, 2Miroljub Todorovic, 3Verica Avramovic, 4Misa Vlahovic and 5Dragan Mihailovic 1ORL Clinic Nis, University Clinical Center Nis, Serbia. 2ORL Clinic Cetinje, University Clinical Center Podgorica, Montenegro. 3Institute for Histology, Medical Faculty Nis, Serbia. 4Clinic for Nephrology, University Clinical Center Nis, Serbia. 5Institute for Pathology, University Clinical Center Nis, Serbia.

Abstract

Objective

Objective is to determine and quantify the production of TNF- in chronic tonsillitis.

Material and Methods

The study comprised of 23 patients with chronic tonsillitis, divided in two groups: 10 patients with tonsillar hypertrophy (TH) with average age 9.0 ± 2.7 years, and 13 patients with recurrent tonsillitis (RT) aged 23.1 ± 5.2 years. Highly sensitive labeled streptavidin-biotin horse reddish peroxidase immunohistochemical method (LSAB+/HRP) was used for detection of TNF- producing cells. Quantification of TNF- was made for crypt epithelium, germinative centers, roundness of follicles, interfollicular areas and subepithelial area. Quantification of lymph follicles and germinative centers included: areal (mm2), median optical density (au), circumference (mm), Ferret diameter (mm), and integrated optical density (IOD).

* Corresponding author: ORL Clinic Nis, Bul. Z. Djindjica 48, 18 000 Nis, Serbia, Tel. +381 18 520 595, E-mail: [email protected] 332 Milan Stankovic, Miroljub Todorovic, Verica Avramovic et al.

Results: Distribution of TNF- producing cells is similar for TH and RT. They are mainly found in subepithelial areas, interfollicular regions, and germinative centers of lymph follicles, and rarely in crypt epithelium. Numerical density of TNF- producing cells is significantly higher in RT, compared to TH.

Conclusion

Quantification of TNF- producing cells confirm domination of cellular Th1 immune response both in TH and RT.

Keywords: Tonsillar hypertrophy, recurrent tonsillitis, tumor necrosis factor, morphometry.

Introduction

Palatine tonsil is involved in active production of cytokines. This soluble protein have a key role in immunity and inflammatory reactions. According to the subtype of cytokine producing T lymphocyte, and the role in immune reactions, they are divided on Th1 and Th2, as well as on proinflammatory and anti-inflammatory cytokines. Tumor necrosis factor (TNF- ) is a cytokine that is important for immune response and allergic reactions.[1] TNF- is a mediator of local inflammatory response causing cascade reaction of cytokines, increased vascular permeability, and enables accumulation of macrophages and neutophyles.[2] It was confirmed that palatine tonsils produce both Th1 (interleukin-2, interferon-γ, TNF- ), and Th2 (interleukin 4, 5, 6, and 13) with predomination Th1 cytokines. [3-8] During infections Th1 cytokines are the first to be produced, with later formation of Th2 type. [9-10] Production of cytokines in tonsillar mononuclear cells is amplified after stimulation with mitogen, or antigen. [6,9,10] Cytokines from palatine tonsils are regulators and modulators of immune response on pathogenic agents, especially during acute phase, and in repeated infections.[3] The aim of the present study is to determine and quantify the presence of TNF- producing cells, as a representative of Th1 cytokines, in chronic tonsillitis.

Materials and Methods

The study comprised of 23 patients with chronic tonsillitis, divided in two groups: 10 patients with tonsillar hypertrophy (TH) with average age 9.0 ± 2.7 years, and 13 patients with recurrent tonsillitis (RT) aged 23.1 ± 5.2 years. [11] Indications for tonsillectomy were based on anamnesis, clinical presentation and laboratory tests. During surgical treatment the patients were without acute infection or antibiotic treatment. Removed palatine tonsils were rinsed in physiological saline, and fixed for 24 hours in buffered formaldehyde. Highly sensitive labeled streptavidin-biotin horse reddish peroxidase immunohistochemical method (LSAB+/HRP) was used for detection of TNF- producing

Distribution of Tumor Necrosis Factor Producing Cells in Chronic Tonsillitis 333 cells. Monoclonal anti-human antibodies, and 3,3`-diamino-bensidine as chromogen were applied. Tonsillar slices 4 m thick were mounted on adherent plates (Super Frost Plus, Menzel-Glaser, Deutschland), dried for one hour at 560C. Primary antisera were diluted (DAKO Antibody diluent, S0809, Denmark). Tissue samples were deparafined, and rehydrated under pressure for 2 minutes in 0.01M citrate buffer, pH 6 (Target Retrival Solution, S 1700, DAKO). After unmasking the antigens, endogen paroxydase was blocked using 3% aqueous H2O2 for 10 minutes at room temperature. Incubation with primary antigen (60 minutes), than incubation with biotinized anti-goat immunoglobulin (30 minutes), and incubation with streptavidine conjugate (30 minutes) were than performed. For visualization of antigen-antibody complex we used 3-amino-9-etilcarbasol (DAKO AEC+ Substrate / Chromogen System, 01475) for 10 minutes. Meyer hematoxylin (Merck, Deutschland) served for nuclear dying. Control of quality and specificity of process was tested using positive and negative control (UK National External Quality Assessment for Immunocytochemistry). [12] Quantification of TNF- was made on the same tissue samples, separately for crypt epithelium, germinative centers, roundness of follicles, interfollicular areas and subepithelial area. Digital pictures 1280x960 pixels using microscope NU-2 (Carl Zeiss, Jena), with objective x25 (NA=0.50), and web camera MSI 370i with test area 0.02 mm2 were used. Numerical areal density (NA) was calculated according to formula: NA=N/At (N- number of TNF- cells, At- test area). Numerical volume (NV) represented: NV=NA/(t+D-2h), (t- thickness of sample, D- diameter of TNF- cells amounting 13 m, h- height amounting 2 m). The number of digital pictures for testing was calculated according to formula: n=(20s/xˉ)2, where: s-standard deviation of numerical density, xˉ- mean numeric density, and it amounted 240. [13] Quantification of lymph follicles and germinative centers included: areal (mm2), median optical density (au), circumference (mm), Feret`s diameter (mm), and integrated optical density (IOD). They were determined using objective x4 (NA=0.1), Image J program of manually edited picture on 70 areas, according to previous formula. Statistical analyze was performed using SIGMASTAT and ORIGIN programs. Statistical significance was determined with Student`s t test, ANOVA test, and Mann-Whitney Rank sum test.

Results

In tonsillar hypertrophy (TH) TNF- producing cells were present predominantly in subepithelial areas, on the border between crypt epithelium and subepithelial lymphatic tissue. Intraepithelial localization was rare. On the other side, nearly all germinative centers of enlarged lymph follicles contained TNF- cells. Interfollicular areas and connective septa had occasional TNF- cells. Mantle areas were without signs of their presence (Figure 1-3.). In recurrent tonsillitis (RT) TNF- producing cells were mostly found in subepithelial areas as cellular aggregates and bands. They are also present in interfollicular areas towards crypt epithelium, whereas in lymph follicles and intraepithelially they were scant. Germinative centers contain small number of TNF- cells. At the border of germinative centers and mantle areas their distribution is linear, forming rings (Figure 4-6.). 334 Milan Stankovic, Miroljub Todorovic, Verica Avramovic et al.

Figure 1. Tonsillar hypertrophy. TNF- producing cells are localized subepithelially, group of cells in germinative center, occasional cells are present in crypt epithelium and in interfollicular areas (LSAB/HRP x100).

Figure 2. Tonsillar hypertrophy. Numerous TNF- producing cells seen in germinative centers, rare cells are near connective septa (LSAB/HRP x100).

Figure 3. Tonsillar hypertrophy. TNF- producing cells mainly in germinative centers, few cells in mantle area (LSAB/HRP x200).

Distribution of Tumor Necrosis Factor Producing Cells in Chronic Tonsillitis 335

Figure 4. Recurrent tonsillitis. Visible lymph follicles. TNF- producing cells are located subepithelially, ratricularly towards crypt epithelium (LSAB/HRP x50).

Figure 5. Recurrent tonsillitis. TNF- producing cells seen mainly around lymph follicles and subepithelially, rarely in crypt epithelium (LSAB/HRP x100).

Figure 6. Recurrent tonsillitis. TNF- producing cells are visible subepithelially and at the border of germinative centers and mantle areas (LSAB/HRP x100). 336 Milan Stankovic, Miroljub Todorovic, Verica Avramovic et al.

Table 1. Numerical areal density (NA) of TNF- producing cells (mean ± standard deviation) in tonsillar hypertrophy (TH) and recurrent tonsillitis (RT).

MORPHOLOGICAL AREA TH RT p Crypt epithelium 67.3 ± 20.8 117.0 ± 37.5 0.01 Germinative center 1652.7 ± 479.3 1526.1 ± 442.6 0.51 Interfollicular area 436.4 ± 148.4 1298.9 ± 293.8 0.001 Subepithelial area 2661.8 ± 485.9 3121.6 ± 556.9 0.05

Table 2. Numerical volume density (Nv) of TNF- producing cells (mean ± standard deviation) in tonsillar hypertrophy (TH) and recurrent tonsillitis (RT).

MORPHOLOGICAL TH RT p AREA Crypt epithelium 4851.8 ± 1358.5 8152.2 ± 2282.6 0.01 Germinative center 119137.5 ± 38124.0 108152.2 ± 34608.7 0.47 Interfollicular area 31603.8 ± 8849.1 70962.7 ± 19869.6 0.001 Subepithelial area 188881.4 ± 26553.2 222981.4 ± 39123.2 0.05

Table 3. Quantification of lymph follicles (mean ± standard deviation) in tonsillar hypertrophy (TH) and recurrent tonsillitis (RT).

PARAMETERS TH RT p Areal (mm2) 0.32 ± 0.09 0.20 ± 0.06 0.001 Optical density 0.38 ± 0.02 0.41 ± 0.02 0.01 Diameter of follicles (mm) 2.04 ± 0.64 1.60 ± 0.22 0.001 Circularity of follicles 0.89 ± 0.06 0.91 ± 0.06 0.43 Ferret diameter (mm) 0.75 ± 0.10 0.59 ± 0.08 0.001 Integrated optical density 0.12 ± 0.03 0.08 ± 0.02 0.001

Table 4. Quantification of germinative centers (mean ± standard deviation) in tonsillar hypertrophy (TH) and recurrent tonsillitis (RT).

PARAMETERS TH RT p Areal (mm2) 0.19 ± 0.08 0.10 ± 0.04 0.001 Optical density 0.35 ± 0.10 0.36 ± 0.07 0.87 Diameter of follicles (mm) 1.60 ± 0.31 1.13 ± 0.17 0.001 Circularity of follicles 0.89 ± 0.05 0.86 ± 0.05 0.96 Ferret diameter (mm) 0.59 ± 0.14 0.42 ± 0.08 0.001 Integrated optical density 0.07 ± 0.02 0.04 ± 0.01 0.001

Quantification of TNF- producing cells indicated on statistical significance for numerical areal density (NA) (ANOVA, Wilks lambda 0.46; Rao R 27.91). Student‘s t test confirmed highly significant differences of NA for crypt epithelium and interfollicular areas,

Distribution of Tumor Necrosis Factor Producing Cells in Chronic Tonsillitis 337

as well as significant differences of NA for subepithelial areas, but not for germinative centers in TH compared to RT (Table 1.). Subepithelial areas and germinative centers were the sites with predominant presence of TNF- producing cells in both groups of patients (56% for TH and 52% for RT in subepithelial areas; 35% for TH and 25% for RT in germinative centers), with their significantly higher number in interfollicular regions for RT and reduced number in germinative centers.

Numerical volume density (NV) of TNF- producing cells confirmed highly significant differences for interfollicular regions, significant for crypt epithelium and subepithelial regions, but not for germinative centers (Table 2.) Percentual distribution of TNF- producing cells was adequate to analyze of NA. Quantification of size of lymph follicles and their germinative centers resulted in significant differences between TH and RT for all analyzed parameters, except for roundness of follicles. Areal, circumference, diameter, and integrated optical density of lymph follicles were significantly higher in TH compared to RT, while optical density showed inversed values (Table 3.). Morphometry of germinative centers of lymph follicles also confirmed higher values of parameters in TH, than in RT (Table 4.).

Discussion

In this study the distribution of TNF- producing cells was mainly subepithelial, and in germinative centers, while in crypt epithelium and mantle areas they were rare. This is similar to other papers. [6,14] Contrary to this, some investigators consider verification of intracytoplasmatic cytokines in tonsils very difficult,[10] others found cytokines mainly in mantle areas and extrafollicularly. [15] The differences in distribution of cytokines in palatine tonsils can be attributed to different methods for verification of cytokine producing cells, with unequal specificity and sensitivity. [10,16] Since the distribution of TNF- producing cells was similar in TH and RT, quantification was very important for detection of mutual differences. Measurements of NA and NV confirmed that TNF- producing cells were in 55% in subepithelial areas, in 30% in germinative centers, in 13% in interfollicular areas, and in 2% in crypt epithelium in both analyzed groups of chronic tonsillitis. Semiquantitative study of Agren et al, (1995, 1996) [5,6] found their predomination in germinative centers with bigger number in RT than in TH, as in our study. Since cytokines are locally produced on the site of infection, the distribution of TNF- production cells in different morphological compartments of palatine tonsils can contribute to better understanding of immune reactions duing antigen stimulation in chronic tonsillitis. Immune reaction is initiated in crypt epithelium, so it is infiltrated with B lymphocytes, and less with T lymphocytes, mostly CD4+ cells.[17] Intraepithelial localization of TNF- producing cells correspond to activated T lymphocytes and macrophages (their production by B cells was not documented). Ageing[18] and chronic tonsillitis[19,20] cause change in distribution of intraepithelial lymphocytes, what may explain the differences between some authors. 338 Milan Stankovic, Miroljub Todorovic, Verica Avramovic et al.

Predomination of TNF- producing cells in subepithelial areas, found in our study, and in some other studies[6] confirms that subepithelial regions represent the site for contact of antigens and immunocompetent cells. [21] Numerous T lymphocytes, mainly CD4+, are present there, migrating from extrafollicular areas towards crypt epithelium.[22] IgA and IgG producing cells are also localized subepithelially, indicating possible role of TNF- for producing other cytokines important for differentiation and secretion of Ig-producing cells. It is supposed that TNF- stimulate clonal selection of activated CD4+ lymphocytes with subsequent influence on cellular, and indirectly on humoral immunity. [23,24] Since TH usually lacks signs of inflammation, TNF- in TH is reduced compared to RT. [11,23,24] Extrafollicular areas besides T lymphocytes contain interdigitant dendritic cells, B lymphocytes, and plasma cells, representing the site of interaction of Th cells, antigen presenting cells, and B lymphocytes. [23] The presence of TNF- cells, both in TH and in RT, indicates their role in producing activated Th cells. Recent studies confirmed that in the beginning of tonsillar inflammation TNF- are produced by Th1 cells and activated macrophages. [25] Macrophages and dendritic cells are universally present in palatine tonsils, but localization in germinative centers is characteristic for hyperplastic follicles in TH. [24] The role of macrophages in germinative centers of lymph follicles is preominantly in phagocytosis of apoptotic cells, mainly centrocytes that failed clonal selection during differentiation in plasma cells. [19,23] Thus, the presence of numerous TNF- producing cells in germinative centers can represent activated macrophages, and Th cells. Ring like distribution of TNF- cells on the border of germinative center and mantle area corresponds to Th cells and follicular dendritic cells. [19] We found no significant difference in numeric density of TNF- producing cells in germinative centers in TH and RT group, although morphometry indicated on significantly bigger lymph follicles (areal and circumference) in TH, compared to RT. Similar values of numerical density of TNF- cells in TH and RT suggest that tonsils in RT retain immunological competence. The presence of abundant TNF- cells in germinative centers confirms their activity, and immune response to specific antigen. This was also found in other studies,[3] where Th cells and follicular dendritic cells in germinative centers produce many cytokines, TNF- as well, with stimulation of differentiation of B cells. Frequent microbial causes of RT are streptococcus pyogenes and hemophylus influenzae. It was documented that membrane M protein from streptococcus pyogenes strongly stimulates TNF- production[10,26] Thus, bigger number of TNF- producing cells in RT can be explained by constant antigen stimulation and inflammation. Contrary to this, TH affects younger population, without morphological signs of inflammation. [11] Recent studies have confirmed that antigen stimulation and mitogen cause increased cytokine formation, primarily TNF- , interferon-γ, and interleukin 6. [6,13] TNF- production is higher in RT, then in TH, both in our, and in other investigations. [5,25,26]

Conclusion

Distribution of TNF- producing cells is similar for TH and RT. They are mainly found in subepithelial areas, interfollicular regions, and germinative centers of lymph follicles, and

Distribution of Tumor Necrosis Factor Producing Cells in Chronic Tonsillitis 339 rarely in crypt epithelium. Numerical density of TNF- producing cells is significantly higher in RT, compared to TH. This data confirm domination of cellular Th1 immune response both in TH and RT.

References

[1] Rink, L; Kirchner, H. Recent progress in the tumor necrosis factor-alfa field. Int Archives of Allergy and Immunol, 1996, 111, 199-209. [2] Strieter, R; Kunkel, S; Bone, R. Role of tumor necrosis factor-Alfa in disease states and inflammation. Critical Care Medicine, 1993, 21 (Suppl 10), S447-S463. [3] Toellner, KM; Toellner, DS; Sprenger, R; Duchrow, M; Trumper, LH; Ernst, M; Flad, HD; Gerdes, J. The human germinal centre cells, follicular dendritic cells and germinal centre T cells produce B cell-stimulating cytokines. Cytokine, 1995, 7, 334-354. [4] Tsunoda, R; Cormann, N; Heinen, E; Onozaki, K; Coulie, P; Akiyama, Y; Yoshizaki, K; Kinet-Denoel, C; Simar, LJ; Kojima, M. Cytokine produced in lymph follicles. Immunol Lett, 1989, 22, 129-134. [5] Agren, K; Andersson, U; Nordlander, B; Nord, CE; Lindae, A; Ernberg, I; Andersson, J. Upregulated local cytokine production in recurrent tonsillitis compared with tonsillar hypertrophy. Acta Otolaryngol (Stockh), 1995, 115, 689-696. [6] Agren, K; Andersson, U; Litton, M; Funa, K; Nordlander, B; Andersson, J. The production of immunoregulatory cytokines is localised to the extrafollicular area of human tonsils. Acta Otolaryngol (Stockh), 1996, 116, 477-485. [7] Passali, D; Damiani, V; Passali, GC; Passali, FM; Boccayyi, A; Bellussi, L. Structural and immunological characteristics of chronically inflamed adenotonsillara tissue in chidhood. Clin Diagn Lab Immunol, 2004, 11, 1154-1157. [8] Rostaing, L; Tkaczuk, J; Durand, M; Peres, C; Durand, D; de Preval, C; Ohayon, E; Abbal, M. Kinetics of intracytoplasmic Th1 and Th2 cytokine production assessed by flow cytometry following in vitro activation of peripheral blood mononuclear cells. Cytometry, 1999, 35, 318-328. [9] Komorowska, A; Komorowski, J; Banasik, M; Lewkowicz, P; Tchorsewski, H. Cytokines locally produced by lymphocytes removed from the hypertrophic nasopharyngeal and palatine tonsils. Int J Pediatr Otorhinolaryngol, 2005, 69, 937- 941. [10] Kerakawauchi, H; Kurano, Y; Mogi, G. Immune response against streptococus piogenes in human palatine tonsil. Laryngoscope, 1997, 107, 634-639. [11] Surjan, L; Brandtzaeg, P; Berdal, P. Immunoglobulin systems of human tonsilla II. Patients with chronic tonsillitis or tonsillar hyperplasia: quantification of Ig-producing cells, tonsillar morphometry and serum Ig concentrations. Clin Exp Immunol, 1978, 31, 382-390. [12] Rhodes, A; Miller, KD. Internal quality control and external quality assessment of immunocytochemistry. In: Theory and practice of histological techniques, J. Bancroft, & M. Gamble (Edss), fifth edition, Churchill Livingstone, London, UK, 2002, 465-498. 340 Milan Stankovic, Miroljub Todorovic, Verica Avramovic et al.

[13] Kalisnik, M; Vraspir-Porenta, O; Kham-Lindtner, T; Logonder-Mlinsek, M; Pajer, Z; Stiblar-Martincic, D; Zorc-Pleskovic, R; Trobina, M. The interdependence of the follicular, parafollicular, and mast cells in the mammalian thyroid gland: a review and a synthesis. Am J Anat., 1988, 183, 148-57. [14] Andersson, J; Andersson, U. Characterization of cytokine production in infectious mononucleosis studied at a single-cell level in tonsil and peripheral blood. Clin Exp Immunol, 1993, 92, 713. [15] Hoefakker, S; van‘Erve, EH; Deen, C; van den Eertwegh, AJ; Boersma, WJ; Notten, WR; Claassen, E. Immunohistochemical detection of co-localizing cytokine and antibody producing cells in the extrafollicular area of human palatine tonsils. Clin Exp Immunol, 1993, 93, 223-228. [16] Andersson, J; Abrams, J; Bjork, L; Funa, K; Litton, M; Agren, K; Andersson, U. Concomitant in vivo production of 19 different cytokines in human tonsils. Immunology, 1994, 83, 16-24. [17] Brandtzaeg, P; Surjan, Jr; Berdal, P. Immunoglobulin systems of human tonsils I. Control subjects of various ages: quantification of Ig producing cells, tonsillar morphometry and serum concentrations. Clin Exp Immunol, 1978, 31, 367-381. [18] Bergler, W; Adam, S; Gross, HJ; Hormann, K; Schwartz-Albiez, R. Age-dependent altered proportions in subpopulations of tonsillar lymphocytes. Clin Exp Immunol, 1999, 116, 9-18. [19] Perry, ME. The specialised structure of crypt epithelium in the human palatine tonsil and its functional significance. J Anat, 1994, 185, 111-127. [20] Lopez-Gonzales, MA; Sanchez, B; Mata, F; Delgado, F. Tonsillar lymphocyte subsets in recurrent acute tonsillitis and tonsillar hypertrophy. Int J Pediatric Otorhinolaryngol, 1998, 43, 33-39. [21] Spencer, J; Perry, ME; Dunn-Walters, DK. Human marginal – zone B cells. Immunol Today, 1998, 19, 421-426. [22] Favre, A; Poletti, M; Marzoli, A; Pesce, G; Giampalmo, A; Rossi, F. The human palatine tonsil studied from surgical specimens at all ages and various pathological conditions. Z Mikrosk Anat Forsch, 1986, 100, 7-33. [23] Brandtzaeg, P. Immunology of tonsils and adenoids: everything the ENT surgeon needs to know. Int J Pediatric Otorhinolaryngol, 2003, 6751, 569-576. [24] Avramović, V; Vlahović, P; Savić, V; Stanković, M. Localisation of ecto 5‘ nucleotidase and divalent cation activated ecto ATP-ase in chronic tonsillitis. ORL, 1998, 60, 174-177. [25] Wakashima, j; Harabuchi, Y; Shirasaki, H. A study of cytokine in palatine tonsil- cytokine mRNA expression determined by RT-PCR. Nippon Jibiinkoka Gakkai Kaiho, 1999, 102, 254-264. [26] Agren, K; Brauner, A; Andersson, J. Haemophilus influencae and streptococcus puogenes group A challenge induce a Th1 type of cytokine response in cells obtained from tonsillar hypertrophy and recurrent tonsillitis. ORL, 1998, 60, 35-41.

Chapter XVII

Peritonsillar Abscess

Olaf Zagólski Diagnostic and Therapeutic Medical Centre ‗Medicina‘, ENT Department, Kraków, Poland.

Abstract

Peritonsillar abscess (quinsy) is a complication of acute bacterial tonsillitis. Its treatment remains controversial. Needle drainage of the abscess may provide an alternative to incision or tonsillectomy. An important element of controversy is the choice of antibiotics after surgical drainage of the abscess. Results of many studies support the resistance of grown bacteria to many antibiotics and the potential importance of anaerobic bacteria in development of peritonsillar abscesses. Although bacteria grown from the pus vary among the continents, clinical implications resulting from the microbiological studies are similar. Patients with peritonsillar abscesses should be treated with antibiotics effective against both aerobic and anaerobic bacteria. In the routine management of peritonsillar abscess, bacteriologic studies are unnecessary on initial presentation. It is, however, necessary to consider infection with anaerobes. Therefore, penicillin and metronidazole are recommended as the antibiotic regimen of choice in the treatment of peritonsillar abscesses. If this treatment is ineffective, broad-spectrum antibiotics (clinadmycin) should be administered.

Introduction

Peritonsillar abscess (quinsy) is a reservoir of pus collected in the peritonsillar space, limited by the superior pharyngeal sphincter and the capsule of the tonsil [1], developing as a complication of bacterial tonsillitis [2, 3, 4]. Most rise secondary to an oropharyngeal or dental infection. Additional factors, such as smoking and periodontal disease, may also contribute to the formation of a peritonsillar abscess [3, 5]. The disease is in the majority of cases unilateral [6]. Diagnosis is clinical—in doubtful cases confirmed with biopsy or 342 Olaf Zagólski computed tomography [3, 7]. When no pus is identified on incision and drainage, the diagnosis of peritonsillar cellulitis is established [8]. The estimated annual incidence of peritonsillar abscesses is 30 cases per 100,000 inhabitants [9, 10]. Currently, less than 20 % of all peritonsillar infections occur in the pediatric population. [7, 11, 12]. About 10% of peritonsillar abscesses recur [9]. The true incidence of bilateral peritonsillar abscesses is unknown, but the incidence of unsuspected contralateral peritonsillar abscess identified at tonsillectomy has been reported to be between 1.9% and 24% [6]. The diagnosis of bilateral peritonsillar abscesses should be considered when the clinical presentation suggests the diagnosis of peritonsillar abscess, but the physical examination reveals bilateral swollen tonsils with a midline uvula [6]. The fact that peritonsillar abscesses develop only in some patients, still has to be explained. Many pus samples contain inflammatory cells in abundance but they are mostly deformed and only occasionally can intracellular bacteria be recognized. Insufficient immunoglobulin-coating of bacteria might be an important aetiopathogenic factor in the development of a peritonsillar abscess [13].

Treatment of Peritonsillar Abscess

The treatment of peritonsillar abscess remains controversial [14]. Adequate drainage with accompanying antimicrobial therapy and hydration are the cornerstones of management. Catheter or needle drainage of these abscesses may provide an alternative to open procedures and is the drainage method of choice for peritonsillar abscesses. There is also a limited but useful place for immediate tonsillectomy in the treatment of this disease [3, 9, 15]. The presumption that the abscess can be drained not only by otorhinolaryngologists, but also by general or emergency care specialists should be verified by the close proximity of the internal carotid artery—a distance of about 1 cm from the tonsillar capsule [9]. Peritonsillar abscess can be successfully treated by three-point puncture and aspiration. The results (recurrence in 19%) are comparable with published data on drainage of the peritonsillar space through the incision procedure. If the bacterial culture shows mixed aerobic and anaerobic flora, but not S. pyogenes, and if the patient has a history of recurrent tonsillitis, incision or proceeding directly to tonsillectomy may be the best therapeutic choice [1]. An important element of controversy is the choice of antibiotics after surgical drainage of the abscess [14]. Intramuscular or intravenous route is used [16]. Antibiotics prevent spread of the infection, which leads to a descending process with consecutive mediastinitis and/or sepsis as a life- threatening condition [4]. Antibiotic therapy started for tonsillitis does not prevent the occurrence of peritonsillar abscess in 45% of patients and has no influence on the clinical course of the disease [2]. However, in selected cases, medical therapy alone, especially in children, can resolve parapharyngeal and hypopharyngeal abscesses [3]. Ancillary use of steroids reduces morbidity in patients with a peritonsillar abscess [3, 7]. Admission to the hospital is not always necessary if a correct outpatient control is possible [10]. Proper hydration, oral and in some cases intravenous, is necessary as some patients may develop dysphagia [17].

Peritonsillar Abscess 343

Obtaining Pus for Microbiological Examination

Proper management of the material from peritonsillar abscesses is very important to establish the pathogen and it should be obtained by aspiration in order to prevent contamination with nasopharyngeal and throat bacteria [18, 19]. At least 3 ml of pus are required [20]. The material for aerobic culture should be transferred to transport basis. Pus to be cultured for anaerobic bacteria must be sent to the laboratory immediately after aspiration in a hermetically closed syringe [20, 21].

Bacteriology of Peritonsillar Abscesses

Streptococcus pyogenes (Group A beta-streptococcus) is commonly considered an important pathogen in this infection [22]. However, recent studies have demonstrated the recovery of many other streptococci mainly consisting of alpha-streptococci [22]. As antibiotics are being used widely, normal flora such as the Streptococcus milleri group has become an important pathogen in peritonsillar abscesses due to an imbalance between organisms and host defense [22]. The Streptococcus milleri group, consisting of 3 species of Streptococcus constellatus, Streptococcus intermedius, and Streptococcus anginosus, forms part of the normal flora most commonly found in the mouth, throat, gastrointestinal tract, and genital tract. These species have become known as an important pathogen in abscess disease but little attention has been paid to their role in peritonsillar abscesses [22]. Many authors stress the importance of anaerobic bacteria in development of peritonsillar abscesses, both in mixed flora and as exclusive agents [13, 18, 19, 22, 23, 24]. Some anaerobic bacteria possess interfering capability with Group A beta-hemolytic streptococci and other pathogens [23]. Peritonsillar abscesses containing beta-haemolytic streptococci Group A, which appear as a single species, contain fewer bacteria per ml than effusions harboring a mixed flora [25]. The possible role of anaerobes in the acute inflammatory process in the tonsils is supported by several observations: anaerobes have been isolated from the cores of tonsils in patients with recurrent Group A beta-hemolytic streptococcal and non- Group A beta-hemolytic streptococcal tonsillitis; the recovery of anaerobes as predominant pathogens in abscesses of tonsils, in many cases without any aerobic bacteria; their recovery as pathogens in well- established anaerobic infections of the tonsils (Vincent's angina), and of their neck complications [23]. Haeggstrom et al. [19] established that all bacteria isolated from peritonsillar abscesses were susceptible to penicillin V, ampicillin and erythromycin when tested in vitro, as some anaerobic bacteria are sensitive to penicillin. However, sensitivity in vitro does not always reflect sensitivity in vivo [19]. Cherukuri et al. [26] observed that the majority of grew organisms were penicillin-resistant. Only a limited number of microbiological studies assessing the bacterial flora of peritonsillar abscesses has been performed and their results seem contradictory [13, 18, 19, 22, 23]. The differences might mainly result from diversity of the bacterial flora in different regions of the world.

344 Olaf Zagólski

Differences of Bacterial Flora of Peritonsillar Abscesses in Different Regions of the World

The results of bacteriological studies presented by several authors differ considerably. In the USA, Brook et al. [18] analyzed 34 peritonsillar abscesses. A total 107 bacterial isolates (58 anaerobic, and 49 aerobic and facultative) were recovered, accounting for 3.1 isolates per specimen (1.7 anaerobic, and 1.4 aerobic and facultatives). Anaerobic bacteria only were present in 6 (18%) patients, aerobic and facultatives in 2 (6%), and mixed aerobic and anaerobic flora in 26 (76%). Single bacterial isolates were recovered in 4 infections, 2 of which were Streptococcus pyogenes and 2 were anaerobic bacteria. The predominant bacterial isolates were Staphylococcus aureus (6 isolates), Bacteroides sp. (21 isolates, including 15 Bacteroides melaninogenicus group), and Peptostreptococcus sp. (16) and Streptococcus pyogenes (10). Beta-Lactamase-producing organisms were recovered from 13 (52%) of 25 specimens tested. In Scandinavia, Haeggstrom et al. [6] tested abscess material from 10 patients with peritonsillar abscesses. A total of 26 bacterial species were isolated from the abscess material; 19 of these were obligate anaerobes. In 4 patients a pure growth of anaerobes was found. In 3 patients a mixed aerobe/anaerobe flora was obtained. In 3 patients a pure growth of aerobes was found. Beta-hemolytic streptococci groups A and C respectively were isolated from 2 patients, but in pure culture from one patient only. In Japan, Fujiyoshi et al. [22] performed bacteriological examination in 31 cases of peritonsillar abscess. The Streptococcus milleri group was most frequently isolated (25.8%), followed by Eikenella corrodens (9.7%), Staphylococcus aureus (6.5%), and Streptococcus pyogenes (3.2%). In Great Britain, Prior et al. [24] examined pus from 53 peritonsillar. A positive culture grew in 85% of quinsies and of these 16% produced aerobes and 84% anaerobes. Penicillin- resistant organisms were grown from 32% of patients and all but one of these organisms (Haemophilus influenzae) was sensitive to metronidazole. The effectiveness of penicillin and metronidazole as the antibiotic regimen of choice in the treatment of peritonsillar abscesses was confirmed in 98% of patients. Sakae et al. [20] examined 39 patients with peritonsillar abscesses. 34 (87%) samples showed positive cultures. Aerobic or facultative aerobic bacteria were isolated from 9 aspirates, mixed aerobic and anaerobic bacteria from 24, and anaerobic bacteria from only 1 aspirate. A total of 69 bacterial isolates (34 aerobic and 35 anaerobic) were recovered. The most common aerobic isolate was Streptococcus sp., with Streptococcus pyogenes being identified in 23% of aspirates. The predominant anaerobic isolates were Prevotella sp. and Peptostreptococcus sp.

Conclusion

Results of the presented studies from various countries confirm that bacterial flora of the peritonsillar abscesses varies between the continents, although clinical conclusions deriving from them are convergent. A comparison of two groups of patients: 58 patients treated with

Peritonsillar Abscess 345 broad-spectrum intravenous antibiotics and 45 patients treated with intravenous penicillin alone, after drainage of the abscess, disclosed that clinical outcomes with respect to hours hospitalized and mean hours febrile were not statistically significantly different between the groups [14]. This indicates that broad-spectrum antibiotics fail to show greater efficacy than penicillin in the treatment of these patients. These results suggest that intravenous penicillin remains an excellent choice for therapy in cases of peritonsillar abscess requiring parenteral antibiotics after drainage [14]. In the cited studies, the obtained aerobic bacteria were usually sensitive to oral penicillin (phenoxymethylpenicillin) [7, 24]. However, in some patients, pathogens resistant to penicillin were also found [24, 26]. Therefore, due to a high probability of infection with anaerobic bacteria, it seems reasonable to administer metronidazole from the beginning of the therapy in all patients with peritonsillar abscess who do not report contraindications to such a regime [24]. The author‘s clinical experience confirms that some of the anaerobic bacteria within pus obtained from peritonsillar abscesses are resistant to metronidazole and sensitive to penicillin and some aerobic bacteria are resistant to penicillin and sensitive to metronidazole. It must be remembered that a high prevalence of penicillin allergy has been reported in patients with peritonsillar abscess [8]. The majority of the infections are resolved by administration of penicillin with metronidazole. In resistant cases a broad-spectrum anaerobic antibiotic (e.g., clindamycin) should be subsequently added [7, 16]. Bacteriologic studies are not necessary in the routine management of peritonsillitis [10, 17]. They should be reserved for patients with a high likelihood of infection by resistant organisms, i.e., diabetics, immunocompromised patients, patients with recurrent peritonsillar abscess, and in cases of further development of the purulent infiltration [26]. It is important to remember that culture for anaerobic bacteria takes up to 10 days.

References

[1] Savolainen, S; Jousimies-Somer, HR; Makitie, AA; Ylikoski, JS. Peritonsillar abscess. Clinical and microbiologic aspects and treatment regimens. Arch Otolaryngol Head Neck Surg, 1993, 119, 521-524. [2] Briner, HR. Does antibiotic therapy hinder the course of peritonsillar abscesses? Schweiz Med Wochenschr, 2000, 125, 14S-16S. [3] Herzon, FS; Martin, AD. Medical and surgical treatment of peritonsillar, retropharyngeal, and parapharyngeal abscesses. Curr Infect Dis Rep, 2006, 8, 196-202. [4] Kinzer, S; Maier, W; Ridder, GJ. Abscess: a Lifethreatening Disease - Diagnostic and Therapeutic Aspects. Laryngorhinootologie, 2007, 86, 371-375. [5] Lehnerdt, G; Senska, K; Fischer, M. Smoking promotes the formation of peritonsillar abscesses. Laryngorhinootologie, 2005, 84, 676-679. [6] Fasano, CJ; Chudnofsky, C; Vanderbeek, P. Bilateral peritonsillar abscesses: not your usual sore throat. J Emerg Med, 2005, 29, 45-47. [7] Garcia, Callejo FJ; Nunez Gomez, F; Sala Franco, J; Marco Algarra, J. Management of peritonsillar infections. An Pediatr (Barc), 2006, 65, 37-43. [8] Chandra, RK; Lee, CE; Pelzer, H. Prevalence of penicillin allergy in adults with peritonsillar abscess. Ear Nose Throat J, 2005, 84, 234-236. 346 Olaf Zagólski

[9] Herzon, FS. Harris, P. Mosher Award thesis. Peritonsillar abscess: incidence, current management practices, and a proposal for treatment guidelines. Laryngoscope 1995, 3 Suppl, 1-17. [10] Palomar Asenjo, V; Borras Perera, M; Ruiz Giner, A; Palomar Garcia, V. Peritonsillar infection. Out-patient management. An Otorrinolaringol Ibero Am, 2006, 33, 399-407. [11] Herzon, FS; Nicklaus, P. Pediatric peritonsillar abscess: management guidelines. Curr Probl Pediatr, 1996, 26, 270-278. [12] Hromadkova, P. Peritonsillar abscess in children. Bratisl Lek Listy, 2006, 107, 272-275. [13] Lilja, M; Raisanen, S; Stenfors, LE. Immunoglobulin- and complement-coated bacteria in pus from peritonsillar abscesses. J Laryngol Otol, 1998, 112, 634-638. [14] Kieff, DA; Bhattacharyya, N; Siegel, NS; Salman, SD. Selection of antibiotics after incision and drainage of peritonsillar abscesses. Otolaryngol Head Neck Surg, 1999, 120, 57-61. [15] Khayr, W; Taepke, J. Management of peritonsillar abscess: needle aspiration versus incision and drainage versus tonsillectomy. Am J Ther, 2005, 12, 344-350. [16] Ozbek, C; Aygenc, E; Unsal, E; Ozdem, C. Peritonsillar abscess: a comparison of outpatient i.m. clindamycin and inpatient i.v. ampicillin/sulbactam following needle aspiration. Ear Nose Throat J, 2005, 84, 366-368. [17] Lamkin, RH; Portt, J. An outpatient medical treatment protocol for peritonsillar abscess. Ear Nose Throat J, 2006, 85, 660-667. [18] Brook, I; Frazier, EH; Thompson, DH. Aerobic and anaerobic microbiology of peritonsillar abscess. Laryngoscope, 1991, 101, 289-292. [19] Haeggstrom, A; Engquist, S; Hallander H. Bacteriology in peritonsillitis. Acta Otolaryngol, 1987, 103, 151-155. [20] Sakae, FA; Imamura, R; Sennes, LU; Araujo Filho, BC; Tsuji, DH . Microbiology of peritonsillar abscesses. Rev Bras Otorrinolaringol, 2006, 72, 247-251. [21] Badran, K. How to avoid spillage of pus when draining peritonsillar abscess. Clin Otolaryngol, 2005, 30, 567-568. [22] Fujiyoshi, T; Inaba, T; Udaka, T; Tanabe, T; Yoshida, M; Makishima, K. Clinical significance of the Streptococcus milleri group in peritonsillar abscesses. Nippon Jibiinkoka Gakkai Kaiho, 2001, 104, 866-871. [23] Brook, I. The role of anaerobic bacteria in tonsillitis. Int J Pediatr Otorhinolaryngol, 2005, 69, 9-19. [24] Prior, A; Montgomery, P; Mitchelmore, I; Tabaqchali, S. The microbiology and antibiotic treatment of peritonsillar abscesses. Clin Otolaryngol Allied Sci, 1995, 20, 219-223. [25] Lilja, M; Raianen, S; Jokinen, K; Stenfors, LE. Direct microscopy of effusions obtained from peritonsillar abscesses as a complement to bacterial culturing. J Laryngol Otol, 1997, 111, 392-395. [26] Cherukuri, S; Benninger, MS. Use of bacteriologic studies in the outpatient management of peritonsillar abscess. Laryngoscope, 2002, 112, 18-20.

Chapter XVIII

Malnutrition and Inflammation- Induced Abnormal Serum Trace Element Concentration in the Patients with Pharyngeal Diseases Who Has Received Enough Trace Elements Intake by Enteral Nutrition

Hitoshi Obaraa, Yasuka Tomiteb and Mamoru Doic aDepartment of Nutrition Management, National Hospital Organization Yamagata National Hospital. bDepartment of Nutrition Management, National Hospital Organization Kamaishi National Hospital. cDepartment of Rehabilitation, National Hospital Organization Kamaishi National Hospital.

Summary

Tube-fed patients with pharyngeal diseases are receiving enough trace elements by intake of enteral formula including rich trace elements. However, serum trace elements concentration shows a low level even if patients are receiving enough trace elements intake. Since trace elements in serum bind to serum protein, serum trace elements concentration is influenced by serum protein concentration. In addition, synthesis of serum protein in the liver is increased or decreased by malnutrition and inflammation. Especially, tube-fed patients with pharyngeal diseases due to stroke are at high risk of malnutrition and aspiration pneumonia. Therefore, evaluation of serum trace elements concentration has to consider influence of malnutrition and inflammation. The trace elements binding protein of the zinc, iron, and copper is albumin, transferrin, and ceruloplasmin, respectively. Serum trace elements concentration positively correlates to each trace elements binding protein. In the case of malnutrition, serum zinc, iron and copper concentration shows low level according to decrease of each 348 Hitoshi Obara, Yasuka Tomite and Mamoru Doi

trace elements binding protein concentration. In the case of inflammation, synthesis of albumin and transferrin are decreased, and serum zinc and iron concentration shows low level. In addition, synthesis of ceruloplasmin is increased, and serum copper concentration shows high level. In the patient with inflammation, serum trace elements concentration normalized with decrease of inflammatory response. As for frequency of abnormal serum trace element concentration in patients with pharyngeal diseases who received tube feeding, low serum zinc concentration was 65%, low serum iron concentration was 43%, and high serum copper concentration was 45%. Most of these patients developed hypoalbuminemia and inflammation. In the analysis of nutritional indices that are predictors of serum trace elements in patients with neurological dysphagia on long-term tube feeding, the predictor of serum zinc concentration was albumin, the predictors of serum iron concentration was transferrin and hemoglobin, the predictors of serum copper concentration was ceruloplasmin and C-reactive protein. The serum zinc, iron, and copper concentration were not correlated to each trace elements intake. In conclusion, abnormal serum trace element concentration in the patients with pharyngeal diseases who has received enough trace elements is induced by malnutrition and inflammation. Iron is required for the synthesis of hemoglobin. Zinc is required for immunocompetence and wound healing. Management of trace elements is extremely important to maintain a good condition for patients. To normalize serum trace element concentration, we recommend treatment of malnutrition and aspiration pneumonia as well as increase in trace elements intake.

Introduction

The tube-fed patients with pharyngeal diseases were at high risk of serum trace elements deficiency, because enteral formula included poor trace elements. It was reported that patients on long-term tube feeding were deficient in iron, copper, and zinc.[1-8] In recent years, enteral formula including rich trace elements were developed to prevent of trace elements deficiency. However, serum trace elements concentration showed a low level even if patients were receiving enough trace elements intake.[9-11] Since trace elements in serum bind to serum protein, serum trace elements concentration is influenced by serum protein concentration.[12-15] The trace elements binding protein of the zinc, iron, and copper is albumin, transferrin, and ceruloplasmin, respectively. In addition, synthesis of serum protein in the liver is increased or decreased by malnutrition and inflammation.[12,14,16,17] The nutritional status of tube-fed patients with pharyngeal diseases can easily worsen. Several studies have reported that serum albumin concentration in tube-fed patients with dysphagia was below 3.5 g/dl.[18-20] The aspiration pneumonia is a common complication occurring in 44-58% of patients receiving tube feeding.[21-23] The inflammation is developed by aspiration pneumonia. Especially, tube-fed patients with pharyngeal diseases due to stroke are high risk of malnutrition and aspiration pneumonia. Therefore, in the tube-fed patients with pharyngeal diseases, evaluation of serum trace elements concentration has to consider influence of malnutrition and inflammation.

Malnutrition and Inflammation-Induced Abnormal Serum Trace Element... 349

Relationship with Serum Trace Elements and Serum Binding Protein

The one of role of trace elements binding protein is transportation of trace elements. The trace elements binding protein of the zinc, iron, and copper is albumin, transferrin, and ceruloplasmin, respectively. As for relationship with serum trace elements and serum binding protein, it was reported that serum trace elements concentration positively correlates to each trace elements binding protein.[9] The Relationship with serum trace elements and serum binding protein in tube-fed patients with pharyngeal diseases were shown in Figure 1-3. Each serum trace elements were positively associated with trace elements binding protein. Especially, there were strong correlation between serum copper and ceruloplasmin, because approximately 90% copper in the serum binds to serum ceruloplasmin. The serum zinc, iron and copper concentration is influenced by each trace elements binding protein.

5.0

4.0

3.0 Albumin (g/dl) Albumin 2.0 y = 0.0274x + 1.7093 r = 0.609 p < 0.001 1.0 30 40 50 60 70 80 90 Serum Zinc (μg/dl)

Figure 1. Relationship with serum zinc and albumin.[9]

500

400

300

200

Transferrin (mg/dl) 100 y = 1.2011x + 157.9 r = 0.594 p < 0.01 0 0 50 100 150 Serum Iron (μg/dl)

Figure 2. Relationship with serum iron and transferrin.[9] 350 Hitoshi Obara, Yasuka Tomite and Mamoru Doi

Ceruloplasmin (mg/dl) 20 y = 0.2328x + 2.1883 r = 0.929 p < 0.001 10 50 100 150 200 Serum Copper (μg/dl)

Figure 3. Relationship with serum copper and ceruloplasmin.[9]

Influence of Malnutrition and Inflammation to Serum Trace Elements

The assessment of nutritional status generally is measuring serum albumin. Albumin is the most abundant serum protein and accounts for approximately 60% of the total serum proteins. The albumin is synthesized in the liver and has many physiological functions. In the malnutrition, protein intake is deficient; as a result, albumin is used for the synthesis of amino acids. Consequently, the amount of proteins stored in the body decreases and hypoalbuminemia develops.[16] In the case of malnutrition, serum albumin concentration is decreased, and serum zinc concentration shows low level.[24] It was reported that tube-fed malnutrition patients exhibited low levels of serum albumin and zinc.[7] Similarly, transferrin and ceruloplasmin are decreased, and serum iron and copper concentration shows low level. The serum zinc, iron and copper concentration is influenced by malnutrition. In the case of inflammation, synthesis of albumin and transferrin in the liver is restrained by inflammatory response. On the other hand, synthesis of ceruloplasmin in the liver is enhanced by inflammatory response. The serum zinc, iron and copper concentration is increased or decreased by inflammation. Relationship with serum trace elements and inflammatory response (C-reactive protein) in tube-fed patients with pharyngeal diseases were shown in Figure 4-6. The serum iron and zinc concentration were negatively associated with C-reactive protein concentration. The serum copper concentration was positively associated with C-reactive protein concentration.[9] In the patients with inflammation, serum copper concentration showed high level, and serum zinc and iron concentration showed low level. There were several reports about similar results.[11,25-28]

Malnutrition and Inflammation-Induced Abnormal Serum Trace Element... 351

10.0 y = －0.0923x + 7.1553

8.0 r = －0.456 p < 0.01

6.0

4.0

2.0 C-reactive protein (mg/dl) 0.0 30 50 70 90 Serum Zinc (μg/dl)

Figure 4. Relationship with serum zinc and C-reactive protein.[9]

10.0 y = －0.0401x + 4.03 r = －0.442 p < 0.01 8.0

6.0

4.0

2.0 C-reactive protein (mg/dl) 0.0 0 50 100 150 Serum Iron (μg/dl)

Figure 5. Relationship with serum iron and C-reactive protein.[9]

10.0 y = 0.0332x －2.5523 r = 0.446 p < 0.01 8.0

6.0

4.0

2.0 C-reactive protein (mg/dl) 0.0 50 100 150 200 Serum Copper (μg/dl)

Figure 6. Relationship with serum copper and C-reactive protein.[9] 352 Hitoshi Obara, Yasuka Tomite and Mamoru Doi

Malnutrition and Inflammation-Induced Abnormal Serum Trace Element Concentration

The nutritional status of tube-fed patients with pharyngeal disease can worsen easily, because patients have several risk factors for malnutrition. The prevalence of hypoalbuminemia, low body weight, and inflammation was 58%, 55%, and 53%, respectively.[9] Many patients developed hypoalbuminemia and inflammation. As for frequency of abnormal serum trace element concentration in patients with pharyngeal diseases who received tube feeding, low serum iron concentration was 43%, high serum copper concentration was 45%, and low serum zinc concentration was 65%.[9] In the many patients, serum trace elements showed abnormal level. These patients were receiving enough trace elements intake. However, serum iron and zinc concentration showed low level. In addition, serum trace elements concentration did not correlate with each trace elements daily intake. There were similar results about relationship with serum trace elements concentration and each trace elements daily intake.[5] The Multiple regression analyses of the predictors of serum trace elements in all subjects are shown in Tables 1-3. In the analysis of nutritional indices that are predictors of serum trace elements in patients with neurological dysphagia on long-term tube feeding, the predictor of serum zinc concentration was albumin, the predictors of serum iron concentration was transferrin and hemoglobin, the predictors of serum copper concentration was ceruloplasmin and C-reactive protein.[9] The zinc, iron, and copper intake were not predictor of each serum trace elements concentration. The serum trace elements concentration is increased or decreased by malnutrition and inflammation, because the serum trace elements binding protein is influenced by malnutrition and inflammation. From these results, it was indicated that abnormal serum trace element concentration in the patients with pharyngeal diseases who has received enough trace elements intake by enteral nutrition was induced by malnutrition and inflammation.

Table 1. Multiple regression analysis of the predictors of serum iron in all subjects.

Independent variables Standardized regression coefficient (β) Albumin 0.133 Transferrin 0.459** Ceruloplasmin 0.215 C-reactive protein 0.140 Hemoglobin 0.405* Lymphocyte 0.047 Body mass index 0.159 Iron intake 0.141 Multiple correlation coefficient (R): 0.764*** Dependent variable: Serum iron *P < 0.05, **P < 0.01, ***P < 0.001

Malnutrition and Inflammation-Induced Abnormal Serum Trace Element... 353

Table 2. Multiple regression analysis of the predictors of serum copper in all subjects.

Independent variables Standardized regression coefficient (β) Albumin 0.122 Transferrin 0.279 Ceruloplasmin 0.913*** C-reactive protein 0.349* Hemoglobin 0.065 Lymphocyte 0.109 Body mass index 0.064 Copper intake 0.061 Multiple correlation coefficient (R): 0.953 *** Dependent variable: Serum copper *P < 0.05, ***P < 0.001

Table 3. Multiple regression analysis of the predictors of serum zinc in all subjects.

Independent variables Standardized regression coefficients (β) Albumin 0.392* Transferrin 0.023 Ceruloplasmin 0.045 C-reactive protein 0.190 Hemoglobin 0.143 Lymphocyte 0.191 Body mass index 0.228 Zinc intake 0.050 Multiple correlation coefficient (R): 0.709** Dependent variable: Serum zinc *P < 0.05, **P < 0.01

Conclusion

In conclusion, abnormal serum trace element concentration in the patients with pharyngeal diseases who has received enough trace elements is induced by malnutrition and inflammation. Iron is required for the synthesis of hemoglobin. Iron deficiency causes anemia. Copper is required for the hematopoietic system and immunocompetence. Copper deficiency causes anemia and depression on immune function. Zinc is required for immunocompetence and wound healing. Zinc deficiency causes depression on immune function, and delay of pressure ulcer. Management of trace elements is extremely important to maintain a good condition for patients. To normalize serum trace element concentration, we recommend treatment of malnutrition and aspiration pneumonia as well as increase in trace elements intake.

354 Hitoshi Obara, Yasuka Tomite and Mamoru Doi

Reference

[1] Skelton, JA; Havens, PL; Werlin, SL. Nutrient deficiencies in tube-fed children. Clin Pediatr, 2006, 45, 37-41. [2] Nagano, T; Toyoda, T; Tanabe, H; Nagato, T; Tsuchida, T; Kitamura, A; Kasai, G. Clinical features of hematological disorders caused by copper deficiency during long- term enteral nutrition. Intern Med, 2005, 44, 554-549. [3] Kaido, T; Hashimoto, H; Okamura, H; Tsukaguchi, K. Progressive severe anemia due to copper deficiency five years after subarachnoid hemorrhage. J Clin Neurosci, 2005, 12, 205-206. [4] Ito, y; Ando, T; Nabeshima, T. Latent copper deficiency in patients receiving low- copper enteral nutrition for a prolonged period. J Parenter Enteral Nutr, 2005, 29, 360-366. [5] Kajiyama, H; Murase, K; Miyazaki, T; Isomoto, H; Fukuda, Y; Yamazawa, N; Soda, H; Takeshima, F; Mizuta, Y; Murata, I; Kohno, S. Micronutrient status and glutathione peroxidase in bedridden patients on tube feeding. J Int Med Res, 2001, 29, 181-188. [6] Iba, K; Kawasaki, I; Yamamoto, H; Uoi, K; Kinoshita, M. Three cases with low levels of serum copper due to long-term enteral nutrition. Jpn J Geriat, 1999, 36, 365-368. [7] Breslow, RA; Hallfrisch, J; Goldberg, AP. Malnutrition in tubefed nursing home patients with pressure sores. J Parenter Enteral Nutr, 1991, 15, 663-668. [8] Henderson, CT; Trumbore, LS; Mobarhan, S; Benya, R; Miles, TP. Prolonged tube feeding in long-term care: nutritional status and clinical outcomes. J Am Coll Nutr, 1992, 11, 309-325. [9] Obara, H; Tomite, Y; Doi, M. Serum trace elements in tube-fed neurological dysphagia patients correlate with nutritional indices but do not correlate with trace element intakes: case of patients receiving enough trace elements intake. Clin Nutr, 2008, 27, 587-93. [10] Saito, M. Ingested trace elements and their blood concentrations in inpatients with enteral liquid food. Biomedical Research on Trace Elements, 2006, 17, 339-341. [11] Oliver, A; Allen, KR; Taylor, J. Trace element concentrations in patients on home enteral feeding: two cases of severe copper deficiency. Ann Clin Biochem, 2005, 42, 136-140. [12] Alan, S. The key role of micronutrients. Clin Nutr, 2006, 25, 1-13. [13] Ito, S; Ishida, Y. Iron, total iron binding capacity, unsaturated iron binding capacity. Nippon Rinsho, 2004, 62(suppl), 288-291. [14] Kodama, H; Gu, Y. Ceruloplasmin. Nippon Rinsho, 2004, 62(suppl), 244-246. [15] Takahashi, M; Kikunaga, S. Nutritional evaluation of minerals: copper, molybdenum, manganese and silicon. Jpn J Nutrition and Dietetics, 1988, 46, 3-13. [16] Shimetani, N. Plasma protein. Nippon Rinsho, 2004, 62(suppl), 203-208. [17] Moshage, HJ; Janssen, JA; Franssen, JH; Hafkenscheid, JC; Yap, SH. Study of the molecular mechanism of decreased liver synthesis of albumin in inflammation. J Clin Invest, 1987, 79, 1635-1641. [18] Leibovitz, A; Sharon-Guidetti, A; Segal, R; Blavat, L; Peller, S; Habot, B. CD4 lymphocyte count and CD4/CD8 ratio in elderly long-term care patients with

Malnutrition and Inflammation-Induced Abnormal Serum Trace Element... 355

oropharyngeal dysphagia: comparison between oral and tube enteral feeding. Dysphagia, 2004, 19, 83-86. [19] Leibovitz, A; Sela, BA; Habot, B; Gavendo, S; Lansky, R; Avni, Y; Segal, R. Homocysteine blood level in long-term care residents with oropharyngeal dysphagia: comparison of hand-oral and tube-enteral-fed patients. J Parenter Enteral Nutr, 2002, 26, 94-97. [20] Okada, K; Yamagami, H; Sawada, S; Nakanishi, M; Tamaki, M; Ohnaka, M; Sakamoto, S; Niwa, Y; Nakaya, Y. The nutritional status of elderly bed-ridden patients receiving tube feeding, J Nutr Sci Vitaminol, 2001, 47, 236-241. [21] Nakajoh, K; Nakagawa, T; Sekizawa, K; Matsui, T; Arai, H; Sasaki, H. Relation between incidence of pneumonia and protective reflexes in post-stroke patients with oral or tube feeding. J Intern Med, 2000, 247, 39-42. [22] Peck, A; Cohen, CE; Mulvihill, MN. Long-term enteral feeding of aged demented nursing home patients, J Am Geriatr Soc, 1990, 38, 1195-1198. [23] Ciocon, JO; Silverstone, FA; Graver, LM; Foley, CJ. Tube feedings in elderly patients. Indications, benefits, and complications. Arch Intern Med, 1988, 48, 429-433. [24] Seeling, W; Ahnefeld, FW; Dick, W; Fodor, L. The biological significance of zinc. Anaesthesist, 1975, 24, 329-342. [25] Cunietti, E; Chiari, MM; Monti, M; Engaddi, I; Berlusconi, A; Neri, MC; De Luca, P. Distortion of iron status indices by acute inflammation in older hospitalized patients. Arch Gerontol Geriatr, 2004, 39, 35-42. [26] Johnson, TE; Janes, SJ; MacDonald, A; Elia, M; Booth, IW. An observational study to evaluate micronutrient status during enteral feeding. Arch Dis Child, 2002, 86, 411- 415. [27] Shenkin, A. Trace elements and inflammatory response: implications for nutritional support. Nutrition, 1995, 11(Suppl), 100-105. [28] Fernandez-Banares, F; Mingorance, MD; Esteve, M; Cabre, E; Lachica, M; Abad- Lacruz, A; Gil, A; Humbert, P; Boix, J; Gassull, MA. Serum zinc, copper, and selenium levels in inflammatory bowel disease: effect of total enteral nutrition on trace element status. Am J Gastroenterol, 1990, 85, 1584-1589.

Chapter XIX

Isolated Uvulitis and the Cannabis Connection

Andrew Gunn School of Medicine, University of Queensland

Abstract

Isolated uvulitis is significant condition that, like the uvula itself, receives relatively little attention. It is commonly, and at times perhaps erroneously, attributed to bacterial infection. The literature documents many other potential causes of uvulitis including smoke and chemical irritation. A recent case of isolated uvulitis associated with smoking cannabis is discussed. The many infective, traumatic and irritant causes of uvulitis are poorly understood and in need of further research.

Introduction

Frequent trouble-makers—for instance, the palatine tonsils—get plenty of attention. Unlike its tonsillar neighbours, the uvula is generally well-behaved and therefore largely ignored. It is possibly best known as the punching bag of cartoon characters swallowed by whales. The uvula‘s function remains under debate [1,2]. It is sometimes regarded as a vestigial organ but it does appear capable of secreting large quantities of fluid saliva [3]. Possible roles of the uvula include moistening and lubricating the throat [2] and performing immunological duties [4]. In addition, the uvula‘s influence on human speech has been noted at least since the time of Hippocrates [5]. Although the impact on English-speakers is often minimal, total uvulectomy may prevent the uvular sounds of languages including French and Arabic [2,6]. Despite this, traditional uvulectomy with its attendant complications of haemorrhage and infection is still widely practiced in the Middle East and Africa [7]. 358 Andrew Gunn

Inflammation of the uvula can cause it to swell to several times its normal size. This can create complaints of an unpleasant gagging or choking sensation at the back of the tongue. Uvulitis is often associated with inflammation of nearby structures, for instance, there may be coexistent tonsillitis, pharyngitis or, less frequently but more seriously, epiglottitis [8,9,10,11]. Isolated uvulitis is less common. Early case reports, in keeping with the views of Aristotle and Hippocrates [5], emphasised the potentially life-threatening nature of inflammation and swelling of the uvula [12]. More recent research suggests mild cases may be relatively frequent and, in the absence of fever and airway compromise, can be treated symptomatically. In one series, all 15 patients followed a relatively benign course [13]. Reported cases of isolated uvulitis have been attributed to a wide variety of causes. These include infection, trauma, allergy, dehydration, snoring, drugs, inhalational irritants, neoplasia and even the sting of an inhaled bee [14]. Determining the cause of uvulitis is sometimes a diagnostic challenge. Most causes of uvulitis result in marked erythema. An exception is allergic uvular oedema. This is usually, but not always [15], said to be pale. The affected uvula has been described as resembling ―a large, white grape‖ [16,17]—in fact, ―uva‖ is Latin for grape. Cases of uvulitis are often ascribed to bacterial infection with group A streptococcus or Haemophilus influenza and treated with antibiotics [18,19,20,21]. In infants, Candida albicans infection has also been implicated as a cause [22]. Traumatic cases are well- documented and uvulitis has followed compression or suction injuries during passage of endotracheal, oral and nasal tubes [23,24]. Snoring and sleep apnoea may also be associated [25]. Other reported possible causes of uvulitis include drug reactions (e.g. regional anaesthesia [26] and ACE inhibitors [27]), saunas [28] and assorted inhalational, thermal and chemical irritants. These include snorting cocaine [29], smoking cocaine [30] and five previous case reports of uvulitis associated with smoking marijuana [31,32,33].

Case Report of Isolated Uvulitis Associated with Marijuana

A young homeless man presented to a health clinic. He complained that, over the past day, his throat had become increasingly painful with an obstructed sensation. On examination, his uvula (see photograph) was very oedematous and red. He had no other significant symptoms or systemic illness and was afebrile. Apart from his uvula and poor oral hygiene, physical examination was normal. He gave a history of multiple long sessions of smoking cannabis through a ―bong‖ (water pipe) over the past few days. When questioned about this he insisted the marijuana was relieving, rather than causing, his throat discomfort. In this case, management was determined by the patient‘s clinical condition and the health care setting, namely a one-doctor clinic based in a community service for the homeless. The patient‘s apparently good health meant no investigations were performed.

Isolated Uvulitis and the Cannabis Connection 359

A sick patient with isolated uvulitis would, however, generally require further assessment. Depending on circumstances, recommended investigations can include a throat swab seeking a causative organism, aerobic and anaerobic blood cultures [34], a full blood examination, imaging of the neck to assess epiglottic involvement and laryngoscopy [17]. The patient was prescribed oral penicillin, told to stop smoking and instructed to attend a nearby hospital emergency department if he developed breathing difficulties. Three days later, he returned to the clinic. He had not taken the penicillin but had greatly reduced his smoking. His throat felt better and the appearance of his uvula was almost normal. Soon after, he completely recovered. In this case, the isolated uvulitis appeared to be exacerbated, if not entirely caused, by excessive smoking of marijuana [35]. Cannabis burns hotter than tobacco and is therefore thought to be more irritant to mucous membranes [36]. The patient came to believe, perhaps correctly, that inhaling hot smoke had damaged his throat, even if a water pipe presumably results in cooler smoke than direct inhalation. A proposed cause of a similar marijuana-related uvulitis was a localised allergy to a chemical constituent of cannabis resin or a contaminant [33]. If cannabis is triggering an allergic reaction, then it seems to create a large, red grape rather than the typical, earlier-mentioned ―large, white grape‖ of uvular allergy.

Conclusion

The uvula is viewed thousands of times by most physicians during their careers. Despite this, it is a surprisingly little understood organ. There remain large gaps in our knowledge of its functions and pathologies. Uvula inflammation, its clinical course and its many infective and irritant causes are poorly understood and in need of further research.

360 Andrew Gunn

Acknowledgement

Thank you to Angela Barnes of Brisbane Youth Service for suggesting the photograph and supplying a camera.

References

[1] Finkelstein, Y; Talmi, Y; Zohar, Y. Readaptation of the velopharyngeal valve following the uvulopalatopharyngoplasty operation. Plastic and reconstructive surgery, 1988, 82(1), 20-30. [2] Back, GW; Nadig, S; Uppal, S; Coatesworth, AP. Why do we have a uvula?: literature review and a new theory. Clinical Otolaryngology & Allied Sciences, 2004, 29, 689- 693. [3] Finkelstein, Y; Meshorer, A; Talmi, YP; Zohar, Y; Brenner, J; Gal, R. The riddle of the uvula. Otolaryngol Head Neck Surg., 1992 Sep, 107(3), 444-50. [4] Olofsson, K; Hellstrom, S; Hammerstrom, M. Human uvula: characterization of resident leukocytes and local cytokine production. Ann Otol Rhinol Laryngol, 2000, 109, 488-496. [5] Fritzell, B. The velopharyngeal muscles in speech. Acta Otolaryngol., 1969, 250(Suppl.), 1-77. [6] Ijaduola, GTA; Williams, OO. Uvulectomy and uvular sound. East Afr Med J., 1984, 61, 490-493. [7] Hunter, L. Uvulectomy: the making of a ritual. South African Medical J., 1995, 85(99), 901-902. [8] Westerman, EL; Hutton, JP. Acute Uvulitis Associated With Epiglottitis. Arch Otolaryngol Head Neck Surg., 1986, 112(4), 448-449. [9] Short, DG; Kitain, DS. Acute uvulitis in combination with acute epiglottitis: a case presentation. Ear Nose Throat J., 1991 Jul, 70(7), 458-60. [10] Jerrard, DA; Olshaker, J. Simultaneous uvulitis and epiglottitis without fever or leukocytosis. Am J Emerg Med., 1996 Oct, 14(6), 551-2. [11] McNamara, R; Koobatian, T. Simultaneous uvulitis and epiglottitis in adults. Am J Emerg Med., 1997 Mar, 15(2), 161-3. [12] Hawke, M; Kwok, P. Acute inflammatory edema of the uvula (uvulitis) as a cause of respiratory distress: a case report. J Otolaryngol., 1987 Jun, 16(3), 188-90. [13] McNamara, RM. Clinical characteristics of acute uvulitis. Am J Emerg Med., 1994 Jan, 12(1), 51-2. [14] Butterton, JR; Clawson-Simons, J. Hymenoptera uvulitis. N Engl J Med., 1987 Nov, 12, 317(20), 1291. [15] Huang, CJ. Isolated Uvular Angioedema in a Teenage Boy . The Internet Journal of Emergency Medicine, 2007, Vol 3, No 2. [16] Reddy, CR; Margolin, SJ. Acute uvular edema. Am J Dis Child, 1983, 137(12), 1204-5. [17] Cohen, M; Chhetri, DK; Head, C. Isolated uvulitis. Ear Nose Throat J., 2007 Aug, 86(8), 462, 464.

Isolated Uvulitis and the Cannabis Connection 361

[18] Li, KI; Kiernan, S; Wald, ER; Reilly, JS. Isolated uvulitis due to Haemophilus influenzae type b. Pediatrics, 1984 Dec, 74(6), 1054-7. [19] Wynder, SG; Lampe, RM; Shoemaker, ME. Uvulitis and Hemophilus influenzae b bacteremia. Pediatr Emerg Care, 1986 Mar, 2(1), 23-5. [20] Aquino, V; Terndrup, TE. Uvulitis in three children: etiology and respiratory distress. Pediatr Emerg Care, 1992 Aug, 8(4), 206-8. [21] Lathadevi, HT; Karadi, RN; Thobbi, RV; Guggarigoudar, SP; Kulkarni, NH. Isolated uvulitis: an uncommon but not a rare clinical entity. Indian Journal of Otolaryngology and Head and Neck Surgery, 2005, 57, 139-40. [22] Krober, MS; Weir, MR. Acute uvulitis apparently caused by Candida albicans. Pediatr Infect Dis J., 1991 Jan, 10(1), 73. [23] Partridge, RA; McNamara, RM. Traumatic uvulitis. Ann Emerg Med., 1992 Nov, 21(11), 1407. [24] Peghini, PL; Salcedo, JA; Al-Kawas, FH. Traumatic uvulitis: a rare complication of upper GI endoscopy. Gastrointest Endosc., 2001 Jun, 53(7), 818-20. [25] Daghistani, KJ. Conditions of the uvula: a 14 years experience Auris Nasus Larynx, 2000, 27(3), 261-264. [26] Neustein, S. Acute uvular edema after regional anesthesia. Journal of Clinical Anesthesia, 2007, 19(5), 365-366. [27] Kuo, DC; Barish, RA. Isolated uvular angioedema associated with ACE inhibitor use. J Emerg Med., 1995, 13, 327-330. [28] Duggal, MS; Main, DM. Acute uvulitis: a sauna hazard. British Dental Journal, 1988, 165, 97-98. [29] Welling, A. Enlarged uvula (Quincke‘s Oedema) – A side effect of inhaled cocaine? – A case study and review of the literature. International Emergency Nursing, 2008, 16(3), 207-210. [30] Macfarlane, R; Hart, J; Henry, J. A man with a massive uvula The Lancet, 2002, 359, 492. [31] Guarisco, JL; Cheney, ML; LeJeune, FE Jr; Reed, HT. Isolated uvulitis secondary to marijuana use. Laryngoscope, 1988, 98, 1309-12. [32] Mallat, AM; Roberson, J; Brock-Utne, JG. Preoperative marijuana inhalation: an airway concern. Can J Anaesth., 1996, 43, 691-3. [33] Boyce, SH; Quigley, MA. Uvulitis and partial upper airway obstruction following cannabis inhalation. Emerg Med (Fremantle), 2002 Mar, 14(1), 106-8. [34] Brook, I. Uvulitis caused by anaerobic bacteria. Pediatr Emerg Care, 1997 Jun, 13(3), 221. [35] Gunn, A. An unusual sore throat. Aust Fam Physician, 2007 Mar, 36, 163. [36] Schwartz, R. Uvular edema and erythema (Letter). Pediatr Infect Dis., 1984, 3, 187.

Index

A adenomas, 8 adenopathy, 163, 164, 198, 202, 203 absorption, 315 adenovirus, x, 193, 194, 195, 196, 207, 208 acceleration, 59, 86 adhesion, 324, 327 accidental, 244 adjustment, 80, 125, 182 accidents, 154, 237 administration, 4, 5, 13, 15, 16, 20, 65, 200, 201, accommodation, 3, 13 225, 284, 345 accounting, 344 adolescence, 196, 215, 229, 232 accuracy, 30, 37, 70, 212 adolescents, 97, 101, 103, 153, 195, 201, 219, 222, ACE inhibitors, 358 229, 230, 231 acetate, 16 adriamycin, 218 acetylcholine, 8, 43 adult population, 194, 195, 201, 203 achalasia, 21, 22, 274 adulthood, 196 achievement, 226 adults, 5, 21, 37, 38, 41, 47, 48, 76, 82, 94, 95, 103, acid, 8, 35 105, 151, 153, 161, 165, 190, 191, 194, 195, 196, acidic, 53 198, 201, 202, 203, 204, 206, 207, 210, 212, 219, acoustic, ix, 34, 103, 109, 121, 131 222, 233, 236, 246, 253, 307, 313, 345, 360 acquisitions, 266 aerobe, 157, 344 actin, 216 aerobic, xiv, 92, 104, 153, 155, 341, 342, 343, 344, action potential, 14, 20 345, 359 activation, 25, 32, 171, 216, 240, 244, 339 aerobic bacteria, 343, 344, 345 active transport, 316 aerodigestive tract, 65, 215, 250, 252, 253, 256, 258 acute glomerulonephritis, 205 aerosols, 145 acute infection, 140, 163, 332 aesthetics, 325 acute ischemic stroke, 73 aetiology, 39, 275, 302 acute lymphoblastic leukemia, 225 afebrile, 11, 358 adaptation, vii, x, 213, 230, 301 Africa, 219, 223, 312, 357 adduction, 66, 71, 134, 172, 179, 292 agar, x, 193, 199, 201, 203, 205, 210 adductor, 21, 22, 76 age, xiii, 10, 11, 36, 60, 69, 87, 97, 118, 121, 141, adenitis, 196 148, 149, 150, 151, 153, 154, 160, 161, 164, 166, adenoidectomy, ix, 3, 4, 38, 39, 48, 82, 109, 114, 195, 196, 198, 204, 208, 211, 215, 218, 219, 232, 115, 131, 150, 152, 154, 164, 165, 166 240, 246, 276, 280, 281, 301, 312, 314, 331, 332 adenoids, 82, 85, 88, 89, 98, 120, 144, 147, 148, 149, agents, vii, xiii, 11, 15, 16, 17, 18, 20, 37, 41, 43, 150, 161, 163, 166, 340 155, 157, 195, 197, 201, 205, 210, 211, 225, 311, adenoma, 251, 257, 261 343 agglutination, 199, 209 364 Index agglutination test, 199 amyloid β, 30 aggregates, 14, 333 amyotrophic lateral sclerosis, 6, 22, 31, 41, 42, 114 aggregation, 29 anaerobic, xiv, 19, 153, 155, 341, 342, 343, 344, aggression, 146, 152 345, 346, 359, 361 aging, 45, 60, 161, 267 anaerobic bacteria, xiv, 153, 155, 341, 343, 344, aging population, 60 345, 346, 361 aging process, 267 anaesthesia, 240, 358 agonist, 30 analgesia, 11 aid, ix, 124, 169, 254 analgesics, 19 AIDS, 208 analog, 240 air, ix, 35, 37, 51, 60, 66, 82, 88, 89, 103, 109, 113, anastomosis, 129 115, 116, 117, 118, 119, 122, 123, 124, 140, 152, anatomy, 18, 35, 39, 44, 64, 77, 119, 130, 148, 161, 153, 154, 182, 236, 264, 273 186, 258, 267, 328 airway inflammation, 264 androgen, 7 airways, 38, 48, 72, 85, 91, 102, 104, 105, 144, 265, anemia, 256, 353, 354 275, 302 anesthesiologist, 256 akinesia, 10, 60 aneurysm, 6, 8, 25, 251, 257, 261 albumin, xiv, 347, 348, 349, 350, 352, 354 angina, 155, 156, 343 alcohol, 34, 314 angioedema, 173, 361 aldolase, 14 angiofibromas, 214 Aldrich syndrome, 226 angiography, 5, 11, 12, 13, 41, 257 alertness, 242 angioplasty, 16, 19 algorithm, 204 angulation, 120 alkaloids, 222 animal studies, 83 ALL, 166 animals, 83, 201, 244 allergic reaction, 332, 359 ankylosis, 17 allergic rhinitis, 85, 88, 99, 150 anorexia, 14, 198, 202 allergy, 91, 345, 358, 359 ANOVA, 333, 336 allograft, 329 antagonist, 31 allografts, 329 anti-acetylcholine receptor, 43 alpha, 29, 153, 343 antibiotic, x, xiv, 19, 141, 193, 194, 200, 201, 212, ALS, 6, 7, 10, 16, 42, 59 332, 341, 344, 345, 346 ALT, xiii, 323, 324, 325, 326, 327 antibiotics, x, xiv, 5, 140, 141, 156, 193, 200, 205, alternative, xiii, xiv, 17, 20, 34, 53, 65, 72, 95, 96, 341, 342, 343, 345, 346, 358 120, 185, 191, 202, 204, 205, 211, 237, 323, 324, antibody, 8, 11, 13, 27, 43, 45, 139, 156, 163, 196, 325, 327, 341, 342 198, 202, 204, 221, 227, 233, 333, 340 alternatives, xiii, 65, 323, 325 anticoagulant, xi, 19, 249, 251, 255, 257, 260 alveolar macrophage, 53 anticoagulation, 16, 260 alveolar macrophages, 53 anticonvulsant, 34 Alzheimer disease, 29, 32, 36, 46 antigen, 45, 138, 196, 198, 204, 205, 221, 312, 332, amaurosis, 13 333, 337, 338 amaurosis fugax, 13 antigen presenting cells, 338 amelioration, 200 antimicrobial therapy, 194, 203, 205, 342 American Academy of Pediatrics, 200, 206, 209 antipsychotics, 35 amino, 333, 350 antitoxin, 4, 5, 14, 20, 200 amplitude, 12, 14, 69, 272, 273 antitumor, 18 amygdala, 30, 50, 156, 157, 163, 164, 165 antiviral, 17, 28, 197, 227 amyloid, 9, 15, 24, 29, 30 antiviral agents, 197 amyloid angiopathy, 24 antiviral therapy, 17, 28, 227 amyloid precursor protein, 29 aortic aneurysm, 261

Index 365 aortic dilatation, 105 ataxia, 11, 12, 21, 24, 34, 35, 44, 47, 226 APA, 118, 119 atherothrombotic, 15, 25 aphasia, 25, 33 Atlas, 131 aphonia, 33 atmosphere, 144, 146 apnea, x, 37, 38, 75, 95, 96, 106, 172, 235, 239, 240, atopy, 99 242, 243, 246 ATP, 340 apoplexy, 251, 261 ATPase, 316 apoptotic, 338 atrial fibrillation, 16 apoptotic cells, 338 atrophy, 7, 10, 11, 14, 15, 30, 34, 37, 41, 129, 145, appendicitis, 141, 150, 153 146, 147, 179, 186, 191, 268 appendix, 156 attacks, 10, 16, 26, 42 apraxia, 33, 34, 123 auscultation, 30, 67, 76, 175 arabinoside, 225 Australia, 49, 183, 190 Arabs, 312 autoantibodies, 40 Arctic, 312 autoimmune, 14, 34, 61, 157 Aristotle, 358 autoimmune disorders, 34 arousal, 36, 94, 96 autonomy, 62 arrest, 15, 20 autopsy, 227 arrhythmia, 180 autosomal dominant, 9, 15, 30 arrhythmias, 237 autosomal recessive, 9 arsenic, 150 availability, 33, 121, 287 arterial hypertension, 24 avoidance, 28, 37, 247, 328 arteries, 24, 25, 325, 329 awareness, 242 arteriography, 12 axonal, 7, 59 arteriosclerosis, 6 axons, 2, 20 artery, xiii, 6, 7, 8, 12, 19, 24, 26, 40, 41, 43, 44, 180, 286, 301, 323, 324, 325, 327, 328, 329, 342 B arthralgia, 215 arthritis, 14, 157 B cell, 14, 337, 338, 339, 340 arthrodesis, 19 B lymphocytes, 139, 157, 159, 226, 337, 338 arthroplasty, 251, 261 B19 infection, 39 articulation, vii, 1, 2, 5, 15, 32, 33, 34, 35, 115, 116, babies, 149, 150, 160 117, 121, 123, 124, 127, 132 bacilli, 153 Asia, 312, 319, 327 bacillus, 201 Asian, 296, 297 back, 27, 112, 117, 133, 238, 358 aspartate, 31 bacteremia, 361 asphyxia, 169, 176 bacteria, xiv, 3, 11, 52, 53, 65, 176, 202, 341, 342, aspirate, 53, 68, 271, 344 343, 344, 345, 346, 361 aspiration pneumonia, vii, viii, xii, xiv, xv, 49, 65, bacterial, vii, x, xiv, xv, 65, 141, 173, 193, 194, 195, 72, 76, 176, 263, 347, 348, 353 203, 205, 206, 211, 214, 341, 342, 343, 344, 346, aspirin, 15, 19 357, 358 assessment, 13, 15, 22, 29, 41, 44, 62, 66, 75, 114, bacterial infection, xv, 194, 205, 211, 357, 358 117, 118, 119, 121, 129, 131, 132, 133, 135, 170, bacterium, 201 175, 187, 215, 216, 221, 225, 262, 265, 275, 301, barium, 120, 175, 183, 266, 268, 269, 271, 272, 274, 314, 328, 339, 350, 359 275, 277, 289 asthenia, 151 barium sulphate, 266 asthma, 63, 83, 88, 91, 102, 264 basal forebrain, 29 asthmatic children, 102 basal ganglia, 2, 7, 11, 28, 29, 32, 50, 55, 60 asymmetry, 118, 120, 171, 313 basal skull fracture, 19 asymptomatic, 12, 16, 37, 55, 57, 196, 199, 200, 203 basilar artery, 24 366 Index

Bax, 189 bone grafts, 17 B-cell, 227, 232, 233 bone marrow, 202, 217, 221, 222, 223, 225, 226, 227 B-cell lymphoma, 232, 233 bone marrow aspiration, 221, 225 behaviours, 117 bone marrow biopsy, 217 beneficial effect, 31, 96, 222 bone marrow transplant, 226, 227 benefits, 11, 17, 18, 56, 91, 198, 200, 289, 327, 355 bone scan, 217, 221 benign, 4, 5, 7, 8, 16, 147, 173, 205, 214, 358 borderline, 122 benign tumors, 8 Boston, 72, 74, 75, 76, 187, 319 beverages, 190 botulinum, 8, 14, 23, 40, 44, 70 bilirubin, 256 botulism, 6, 14, 20, 40 binding, xiv, 8, 9, 15, 347, 348, 349, 352, 354 bowel, 260 bioassay, 14 bradycardia, 15 biochemistry, 64 bradykinin, 195, 207 biofeedback, 69, 77, 131, 134, 178 brain, viii, xii, 7, 17, 30, 32, 49, 54, 55, 59, 74, 171, biofilms, 141, 152, 167 173, 188, 263, 299, 300, 301, 302, 305, 307 biomarker, 30 brain functions, 171 biometric, 98 brain injury, xii, 74, 173, 188, 299, 300, 301, 302, biopsies, 4, 195, 202 305, 307, 308 biopsy, x, 4, 12, 14, 15, 121, 163, 207, 213, 215, brain stem, 173, 263 217, 218, 219, 221, 223, 225, 227, 313, 341 brain structure, 17 bioterrorism, 202 brain tumor, 173 biotin, xiii, 331, 332 brainstem, viii, 2, 3, 7, 8, 10, 21, 22, 23, 24, 25, 28, bipolar, 123, 239, 248 32, 49, 50, 51, 54, 55, 56, 300 birth, 147, 148, 154 Brazil, 1 bleeding, xi, 10, 149, 214, 235, 239, 244, 245, 249, breakdown, 326 251, 255, 256, 257, 258, 260, 313 breathing, vii, viii, xi, 1, 2, 9, 21, 35, 36, 37, 51, 52, bleeding time, 255 60, 63, 75, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, blepharitis, 150 91, 94, 96, 97, 98, 99, 101, 104, 105, 107, 144, blood, xi, 9, 13, 15, 17, 19, 25, 54, 63, 83, 156, 199, 167, 236, 237, 246, 247, 249, 256, 275, 359 201, 202, 203, 205, 210, 211, 225, 235, 236, 237, breathing disturbances, viii, 79, 80 239, 242, 243, 250, 255, 256, 257, 285, 287, 292, broad spectrum, 201 315, 325, 329, 340, 354, 355, 359 bronchial asthma, 102 blood clot, 17 bronchitis, 63, 83, 144, 146, 150, 156 blood cultures, 19, 202, 359 bruit, 13 blood flow, 13, 285, 315, 325 buffer, 145, 333 blood pressure, 15, 17, 25, 237 bulbar, 7, 11, 13, 14, 32, 33, 59, 125, 165 blood pressure reduction, 15, 25 Burkitt‘s lymphoma, 223, 224, 225 blood supply, 54, 285, 292, 325, 329 burn, 61, 75, 326 blood transfusion, 257 burning, xi, 147, 151, 235, 239 blood vessels, xi, 9, 235, 239, 250, 287 burns, viii, 49, 61, 329, 359 bloodstream, 63, 185 bursa, 149, 151 blot, 198 blurring, 3 C BMI, 240 body mass, 37, 240 C. diphtheriae, 4, 199 body mass index, 37, 240 C. pneumoniae, 202 body weight, 352 calcification, 12 bolus, 31, 50, 51, 52, 53, 54, 58, 65, 68, 169, 171, calcium, 8, 14, 20, 129, 135, 154 172, 175, 178, 181, 183, 187, 264, 265, 266, 270, calculus, 154, 155, 164 271, 272, 273, 301, 302 caliber, 13

Index 367 calibration, 267 cell differentiation, 157, 216 calorie, 183 cell organelles, 138 Canada, 133 cellular immunity, 26 cancer, 20, 26, 43, 45, 63, 65, 74, 150, 179, 182, cellulitis, 203, 342 184, 228, 230, 231, 232, 251, 281, 282, 285, 288, cement, 146 290, 296, 297, 319 Centers for Disease Control, 40, 42, 204, 207, 209 cancer treatment, 179 central nervous system, 11, 39, 173, 222, 226, 227, Candida, x, 193, 194, 206, 358, 361 263 candidates, 124 central pattern generator, 28, 54, 172 cannabis, xv, 357, 358, 359, 361 cerebellar ataxia, 11, 12, 24, 34, 35, 47 capsule, 2, 54, 81, 139, 341, 342 cerebellar disorders, 263 carbohydrate, 176, 204, 205 cerebellopontine angle, 56 carbon dioxide, 203, 237 cerebellum, 2, 28, 32, 33, 114 carcinoma, xi, 3, 14, 39, 168, 214, 219, 220, 228, cerebral amyloid angiopathy, 24 230, 231, 232, 233, 249, 262, 281, 289, 290, 292, cerebral arteries, 24 294, 297, 298, 312, 313, 314, 316, 317, 319, 320 cerebral cortex, 307 cardiac arrhythmia, 180, 237 cerebral hemisphere, 32, 300 cardiac involvement, 14 cerebral palsy, 17, 42 cardiopulmonary, 47, 237 cerebrospinal fluid, 3, 214, 217, 221 cardiovascular disease, 242 cerebrovascular, 9, 277 caregivers, viii, 1, 38 cerebrovascular disease, 9, 277 caries, 83, 176 ceruloplasmin, xiv, 347, 348, 349, 350, 352 carotid sinus, 251, 261 cervical laminectomy, 17 carrier, 140, 212 cervical spondylosis, 74 cartilage, 56, 111 channel blocker, 20 cartilaginous, 110, 147, 311 channels, 8, 14, 26, 148 CAS, 46 chemoresistant, 228 case study, 139, 361 Chemotherapy, 225, 227, 231, 284, 314 cat scratch disease, 4 chest, xi, 29, 54, 62, 64, 67, 83, 217, 221, 224, 249, cataracts, 15 252, 253 catecholamine, 18 chewing, 26, 52, 61, 174 categorization, 183 chicken, 261 catheter, 19, 42, 266, 267, 275 childhood, vii, x, 44, 148, 149, 154, 161, 163, 167, catheterization, 12 194, 196, 206, 213, 215, 219, 223, 225, 229, 230, catheters, 8, 19, 127, 128, 275 232, 233 cation, 340 China, 219, 312 cattle, 201 Chlamydia trachomatis, 206 Caucasian, 327 chloride, 316 Caucasian population, 327 cholesterol, 15, 153, 155 causal relationship, 236 cholesterol-lowering drugs, 16 causation, 312 cholinergic, 20, 29 cauterization, 256 cholinergic neurons, 29 cavitation, xi, 11, 235 cholinesterase inhibitors, 31 cavities, 81, 82, 110, 122, 170, 176 chondroma, 173 CDC, 40, 207 chorea, 33, 34, 35, 60 cecum, 164 choreoathetoid movements, 25 cell, 3, 14, 138, 156, 157, 160, 168, 170, 198, 202, chorion, 138, 146 208, 216, 219, 223, 225, 226, 227, 230, 232, 233, chorioretinitis, 156 281, 290, 292, 294, 298, 315, 316, 339, 340 chromatin, 138 cell culture, 198 chromosome, 7, 9, 30, 34, 223, 224, 232 368 Index

Chromosomes, 229 cognitive impairment, 10, 59, 60, 237 chronic disease, 151, 152 coherence, 247 chronic obstructive pulmonary disease, 63, 75 cohort, 75, 189 cilia, 53 colds, 195, 197, 207 CIN, 201 collagen, xi, 31, 35, 142, 235 Cincinnati, 239 college students, 194, 198, 206, 208 ciprofloxacin, 201 Colombia, 101 circulation, 7, 12, 15, 40, 70, 83, 296, 301, 324, 325, colonization, 176 327, 328 colorectal cancer, 26, 45 cisplatin, 222, 232 coma, 22, 308 Cisplatin, 281 combination therapy, 20 classes, 201 communication, 17, 29, 34, 46, 56, 61, 183, 325 classical, 25, 26, 27, 132, 203, 205, 216, 223, 272 community, 80, 87, 246, 308, 358 classification, 27, 41, 47, 113, 170, 172, 216, 217, compensation, 68, 69, 114, 163, 177, 186 219, 220, 222, 223, 225, 282 competence, 297, 338 classrooms, 195 competency, 117 clavicle, 257, 291 complement, 8, 27, 346 cleaning, 144, 147 complete blood count, 225 cleft lip, 102 complete remission, 227 cleft palate, ix, 109, 113, 114, 117, 119, 125, 127, complex interactions, 312 130, 131, 132, 133, 134, 135, 243 complexity, 72, 118, 316 clinical assessment, 306 compliance, 38, 59, 106, 182, 183, 184, 191, 237 clinical diagnosis, 4, 9, 14, 24, 30, 256 components, viii, 3, 8, 36, 46, 79, 80, 84, 110, 112 clinical examination, 4, 24, 212, 215, 305 comprehension, 33, 316 clinical oncology, 315, 316 computed tomography, 85, 103, 221, 232, 313, 316, clinical presentation, 14, 196, 215, 216, 222, 226, 320, 321, 342 258, 332, 342 Computed tomography (CT), xi, 249 clinical symptoms, 22, 271 concentration, xiv, xv, 19, 59, 316, 347, 348, 349, clinical syndrome, 13, 39, 201, 212 350, 352, 353 clinical trial, x, 20, 169, 178, 179, 184, 185, 197, 227 concrete, 177 clinicopathologic correlation, 229 conditioning, 177 clinics, 96 conduction, 11, 37 close relationships, 88 conductive, viii, 79, 80, 88, 89, 102 Clostridium botulinum, 8 conductive hearing loss, viii, 79, 80, 88, 89, 102 closure, viii, 31, 35, 51, 65, 67, 71, 82, 109, 110, configuration, 130, 267 111, 112, 113, 117, 118, 119, 120, 122, 123, 124, conformity, 166 125, 126, 127, 128, 129, 130, 133, 180, 290, 301, confusion, 65, 66, 181 326, 328, 329, 330 Congress, 132 c-myc, 226 conjunctiva, 4 c-Myc, 223 conjunctivitis, 150, 196, 203 CNS, 11, 22, 34, 225, 232 connective tissue, ix, xii, 137, 148, 173, 263 CO2, 247, 248 consanguinity, 118 coagulation, xi, 165, 235, 236, 239, 240, 243 consciousness, 29 coagulum, xi, 235, 239 consensus, 19, 20, 90, 183, 245, 246 cocaine, 358, 361 consent, 149, 240 coccus, 203 conservation, 8 Cochrane, 19, 31, 37, 42, 43, 46, 47, 48, 105, 212 constraints, 55, 218 coding, 47 consumption, 205 cognition, 59 contaminant, 359 cognitive function, 308 contaminated food, 8, 201, 202

Index 369 contamination, 197, 291, 343 cranial mononeuropathy, 4 continuous positive airway pressure, 48, 95, 237 cranial nerve, viii, 2, 7, 8, 10, 11, 18, 24, 28, 29, 33, contractions, 14, 21 39, 41, 49, 50, 54, 56, 110, 114, 173, 174, 214, contracture, xiii, 14, 323, 325, 327 218, 220, 221, 222, 263, 285, 313 control, 2, 9, 15, 17, 18, 28, 29, 30, 31, 35, 39, 45, craniofacial, viii, 79, 80, 81, 85, 87, 89, 94, 97, 98, 46, 47, 50, 54, 55, 59, 69, 70, 72, 98, 105, 114, 99, 100, 101, 102, 105, 134, 236, 243, 280 116, 119, 152, 170, 171, 172, 179, 183, 186, 187, C-reactive protein, xiv, 348, 350, 351, 352, 353 201, 206, 211, 218, 222, 257, 275, 305, 319, 333, creatine, 14 342 creatine kinase, 14 control group, 179 cricothyroidotomy, 256 controlled studies, 95 critical period, 73 controlled trials, 20, 170, 179, 189, 200 critically ill, 277 contusions, 7, 17 cross-sectional, 82, 91 convex, 92, 93 cross-talk, 26 COPD, 63 Crouzon's disease, 85 Copenhagen, 39 crown, 139, 159 copper, xiv, 347, 348, 349, 350, 351, 352, 353, 354, crust, 145 355 crying, 9, 34 corona, 2, 4, 54 crystals, 153 coronary artery disease, 180 CSF, 3, 10, 11, 14, 17, 19, 27, 30, 224 coronavirus, x, 193, 194, 195, 207 CT scan, 12, 17, 119, 224, 257 corpus callosum, 11 cues, 34, 50, 124 correlation, 5, 34, 83, 92, 157, 166, 229, 273, 349, culture, x, 11, 14, 19, 175, 183, 193, 196, 198, 200, 352, 353 203, 204, 205, 211, 215, 342, 343, 344, 345 correlation coefficient, 352, 353 culture media, 11 correlations, 39 cycles, 37, 178 cortex, 2, 6, 23, 24, 28, 29, 32, 50, 54, 55, 59, 171, cyclophosphamide, 20, 218, 225, 232 177, 186, 188 cyclosporine, 18, 20 corticospinal, 59 cyst, 151, 173, 251, 257, 261 corticosteroids, 16, 17, 18, 20, 197, 225 cystic fibrosis, 63 Corynebacterium, x, 193, 194, 199, 209, 210 cystine, 199 Corynebacterium diphtheriae, x, 193, 194, 199, 209 cysts, 152, 153, 154 cosmetic surgery, 326 cytokine, 332, 337, 338, 339, 340, 360 cosmetics, 324 cytokines, 168, 332, 337, 338, 339, 340 cost benefits, 18 cytology, 217, 219, 223 cost-benefit analysis, 99 cytomegalovirus, 195 costs, 72, 245, 275 cytometry, 339 cotton, x, 193 cytosine, 225 cough, 9, 17, 29, 52, 53, 59, 68, 72, 145, 149, 151, cytotoxic, 9, 14 165, 175, 180, 196, 197, 204, 271, 302, 304, 305, 306 D coughing, xi, 9, 26, 29, 52, 64, 68, 146, 151, 162, 174, 199, 249, 251, 271 dairy products, 205 Coumadin, 251 danger, 181, 250, 252 coupling, 115 data analysis, 267 covering, ix, 13, 137, 160, 165, 250, 316 data set, 308 coxsackievirus, 195, 197 deafness, 89, 149, 221 coxsackievirus infection, 195, 197 death, 4, 59, 149, 199, 237, 277, 301, 308 CPAP, 38, 95, 237, 246 debridement, 19, 291 CPG, 54, 56 decibel, 89 370 Index deciduous, 99 developmental milestones, 118 decisions, ix, 19, 65, 67, 109, 129, 150, 170, 265 deviation, 116, 150, 236 decompression, 17, 19, 28 diabetes, 11, 24, 144 defecation, 20, 276 diagnostic criteria, 26, 27 defects, viii, xiii, 9, 13, 49, 110, 113, 116, 280, 285, diaphragm, 36, 186, 191, 225, 236, 250 287, 301, 323, 324, 326, 327, 328, 329, 330 diarrhea, 201, 203 defence, 152 diet, 57, 61, 64, 71, 183, 191, 264, 293, 294 defense, ix, 137, 139, 164, 343 dietary, 15, 30, 64, 182, 219, 312 deficiency, 15, 34, 81, 92, 93, 94, 96, 101, 114, 123, dietary habits, 219 124, 219, 223, 226, 227, 268, 348, 353, 354 differential diagnosis, 7, 34, 45, 202, 211, 230, 254, deficits, 29, 33, 59, 174, 242, 300 261, 312 definition, 80, 119, 215, 305, 306 differential treatment, 130 deformation, 151 differentiation, ix, 137, 138, 157, 216, 219, 338 deformities, 17, 37, 80, 81, 85, 97, 329 diffusion, 4, 10, 275 degenerative disease, 6, 21, 29, 32, 36, 59, 60, 64, 75 digestive tract, 265, 274 deglutition, viii, 30, 71, 74, 76, 79, 80, 110, 144, diluent, 333 150, 163, 164, 165, 171, 214, 264, 267, 270, 276, diphtheria, 3, 4, 5, 39, 146, 195, 199, 200, 202, 208, 277, 306 209 degradation, 8, 29 diplopia, 13, 214 degrading, 157 direct action, 154 dehiscence, 239 direct bilirubin, 256 dehydration, vii, viii, xii, 49, 174, 176, 263, 277, direct observation, 119, 175 308, 358 disabilities, 38, 170 dehydrogenase, 14, 221 disability, 11, 16, 62, 170, 173, 185, 301 dementia, 29, 31, 46, 184, 191, 277 disability progression, 16 demographic factors, 73 discipline, 245 demyelination, 3, 5, 25, 37 discomfort, 22, 27, 238, 358 dendritic cell, 138, 139, 167, 338, 339 disease progression, 198 denervation, 10, 11 diseases, vii, viii, ix, x, xiv, xv, 1, 2, 3, 4, 6, 13, 24, Denmark, 333 31, 35, 36, 38, 39, 49, 57, 63, 88, 91, 114, 144, density, xiii, xiv, 12, 54, 122, 157, 217, 266, 331, 146, 147, 150, 153, 169, 170, 172, 173, 174, 183, 332, 333, 336, 337, 338, 339 197, 213, 225, 347, 348, 349, 350, 352, 353 dental implants, 297 dislocation, 275 dentistry, 80 disorder, 7, 8, 25, 30, 33, 34, 36, 52, 61, 94, 95, 104, dentists, 65, 80 105, 117, 140, 175, 205, 227, 274, 300 dentures, 65 displacement, xi, 17, 119, 125, 249, 255, 268 deoxyhemoglobin, 255 disposition, 138 depolarization, 8 dissociation, 3, 7, 11 deposition, 29 distortions, 314 depression, 311, 353 distress, xii, 27, 214, 224, 227, 259, 279, 289, 360, dermatitis, 292, 294 361 dermatomyositis, 6, 8, 14, 20, 60, 173 distribution, 10, 26, 122, 158, 159, 160, 194, 219, dermis, xiii, 323, 325, 326, 329 223, 312, 315, 333, 337, 338 destruction, 2, 6, 8, 26, 91, 143, 285, 313 diversity, 343 destruction processes, 143 diving, 63 detection, xiii, 11, 13, 14, 15, 118, 199, 200, 202, division, 125, 138 204, 205, 209, 210, 224, 230, 311, 312, 314, 316, dizziness, 256 318, 319, 331, 332, 337, 340 DNA, 27, 198, 202, 312 developed countries, 199, 203 doctors, 87, 164 developing countries, 132, 195, 199 dominance, 55, 171

Index 371 donor, xiii, 129, 286, 323, 324, 325, 326, 327, 328, elderly, 18, 53, 57, 65, 76, 188, 260, 264, 266, 267, 329, 330 276, 277, 296, 354, 355 dopamine, 21, 22, 30, 31 election, 245, 346 dopamine agonist, 30, 31 electrocautery, 243 dopaminergic, 29 electrodes, 69, 70, 123 Doppler, 13 electrolyte, 176 dorsi, 281, 291 electrolyte imbalance, 176 dorsolateral prefrontal cortex, 32 electromyography, 10, 69, 265, 275 dosage, 120, 121, 156 electron, 15, 316 Down syndrome, 114 electron microscopy, 15 downsized, 124 ELISA, 11, 198, 211 drainage, xiv, 19, 144, 152, 257, 341, 342, 345, 346 ELISA method, 211 drinking, 50, 53, 62, 64, 69, 174 emboli, 18, 256, 259 Drought, 6, 7, 11, 42 embolism, 16, 19 DRS, 301 embolization, 18, 256, 259 drug reactions, 358 embryology, 170 drug resistance, 315 emergency medical services, 15, 25 drug therapy, 37 EMG, 10, 11, 13, 14, 70, 123 drug-induced, 22, 35 emission, 30, 71, 115, 116, 117, 118, 124, 132, 171, drugs, xi, 19, 34, 35, 43, 145, 200, 218, 222, 249, 316, 319, 320, 321 358 emotional, 9, 22, 171 drying, 146, 147 emphysema, 83 duration, xii, 19, 20, 55, 68, 69, 75, 178, 180, 185, encephalitis, 7, 11, 173 186, 198, 200, 225, 226, 299, 303, 305, 306 encoding, 21, 34, 36 dust, 144 endocarditis, 141, 153, 156, 201, 210 duties, 357 endocrine, 35, 149 dysarthria, vii, 1, 9, 10, 13, 15, 16, 22, 29, 32, 33, endocrine disorders, 35 34, 35, 46, 47, 59, 123 endocytosis, 8 dyskinesia, 56, 64 endoscope, 175 dysplasia, 85, 100, 221 endoscopy, 4, 119, 121, 133, 151, 165, 175, 361 dyspnea, xi, 74, 163, 226, 249, 250, 252, 254, 255, endotracheal intubation, 20, 125, 260 256 end-to-end, 128 dystonia, 21, 43, 44 endurance, 70, 178, 184 energy, x, xi, 34, 110, 121, 124, 133, 176, 191, 235, E 238, 239 England, 73 ears, 88, 102, 118, 161 enlargement, 17, 85, 145, 200, 203 East Asia, 312 enteritis, 141, 153, 201 eating, viii, 29, 49, 50, 52, 53, 55, 62, 63, 64, 65, 69, enterocolitis, 201 91, 174, 184 enterovirus, 7 EBV infection, 195, 221, 226 enteroviruses, 7, 11, 17 ecchymosis, 13, 252, 253 entorhinal cortex, 30 echocardiogram, 25 enuresis, 37, 149 ectodermal dysplasia, 85, 100 environment, 86, 144, 202, 203 eczema, 157 environmental factors, 81 edema, 4, 8, 10, 17, 28, 41, 195, 239, 360, 361 environmental influences, 81 Education, 185 enzyme immunoassay, 27, 199, 209 effusion, 88, 89, 118 enzymes, 14 Egypt, 109, 296 epidemic, 4, 207, 208, 209 elbows, 14 epidemics, 195, 205 372 Index epidemiologic studies, 88 exercise, 31, 69, 76, 77, 170, 176, 177, 178, 185, epidemiology, 104, 206, 230, 319 188, 189 epidural abscess, 295, 296 exertion, 251 epiglottis, 52, 57, 165, 264, 265, 270 exocytosis, 8 epiglottitis, 173, 252, 358, 360 expansions, 147 epilepsy, 11 expertise, 17, 63, 64, 67 epinephrine, 125 exposure, xiii, 28, 66, 120, 175, 195, 204, 205, 253, episodic memory, 30 323, 324, 325, 326 epistaxis, 13, 214, 313 expulsion, 58, 155 epithelial cells, 26, 153 external oblique, 291 epithelium, ix, xiii, xiv, 137, 138, 146, 147, 157, extracranial, 12, 40 160, 161, 167, 195, 312, 331, 332, 333, 334, 335, extrapyramidal diseases, 33 336, 337, 338, 339, 340 extravasation, 13 Epstein Barr, 319 extrusion, 129, 315 Epstein-Barr virus, x, 4, 193, 194, 207, 208, 223, exudate, 89, 195, 198, 200, 203, 204 230, 233, 251, 257, 262, 312 eye, 10, 13, 237 equilibrium, 226 eyelid, 13 erectile dysfunction, 37 eyes, 204 erosion, 147 erysipelas, 203 F erythema nodosum, 201 erythematous, 157, 196, 197, 200, 201, 203 Facial nerve, 290 esophagitis, 185 facial pain, 13, 26 esophagoscopy, 260 facial palsy, 27 esophagus, xi, 51, 52, 56, 58, 63, 68, 72, 170, 172, facies, 149 180, 181, 190, 249, 275, 289, 297 factor VII, 260 essential fatty acids, 176 failure, 3, 17, 20, 21, 122, 238, 280, 285, 289, 291, esterase, 19 325 esthetics, 86 false negative, 30 estimating, 132, 176 family, 30, 61, 64, 100, 118, 140, 201, 202, 205, etiologic factor, 27 216, 226 etiology, vii, x, 1, 2, 4, 5, 6, 21, 23, 25, 38, 53, 62, family members, 64, 202 85, 99, 113, 134, 193, 194, 203, 236, 265, 275, Fas, 76 298, 301, 312, 361 fascia, 129, 250 Europe, 219, 223, 230 fasciculation, 10 eustachian tube, 110, 311 fat, 31, 35, 135, 139, 153, 154, 155, 327 evacuation, xi, 249, 256 fatigue, 16, 66, 177, 202, 237 evening, 50, 144 fauces, 50, 195 evoked potential, 10 fax, 79 evolution, xii, 145, 146, 152, 153, 155, 255, 299, FDG, xiii, 311, 316, 318, 319, 321 301, 303, 306 feces, 197 examinations, 5, 266, 275 feedback, 32, 36, 70, 124, 185 excision, 18, 123, 225, 241, 245, 257, 291, 296 feeding, xiv, 4, 16, 31, 46, 50, 53, 54, 63, 64, 67, 71, excitability, 26 72, 75, 174, 184, 185, 186, 187, 191, 286, 308, excitation, 165 348, 352, 354, 355 excitotoxicity, 31 feelings, 59 exclusion, 5 feet, 197 excretion, 315 females, 240, 312 execution, 28, 32 fetal, 160

Index 373 fever, 12, 146, 149, 196, 197, 198, 200, 201, 202, fracture, 19, 40, 41, 250, 257, 258, 259 203, 204, 207, 208, 226, 296, 358, 360 fractures, 6, 13, 19, 41, 59, 66, 259 fiberoptic scope, 253 fragmentation, 237 fibers, 2, 6, 9, 15, 23, 110, 111, 126, 185, 191 France, 213, 230 fibrillation, 10, 14, 16 fresh frozen plasma, 257 fibrin, 14, 199 fresh water, 201 fibrinogen, 139 friction, 243 fibroma, 150 frontal cortex, 2 fibrosis, 56, 63, 142, 157, 185, 221, 239, 314 functional approach, 315 fibula, 297 functional magnetic resonance imaging, 71, 171, 187 fidelity, 119 fungal, 7, 18, 173 film, 90, 93, 253, 255, 266 fungal infection, 173 films, 85, 253 fungi, x, 11, 193, 194 filtration, 88, 139 fungus, 141 fine needle aspiration, x, 4, 213 fusion, 8, 29, 57, 74, 215, 216 fish, 127, 261 FISH, 216, 223, 224 G fission, 202 fistulas, 125 gadolinium, 10 fixation, 27, 57 gait, 34 flank, 199 gamma rays, 316 flex, 185 ganglia, 2, 7, 11, 28, 29, 32, 50, 55, 60, 148, 151 flexor, xiii, 14, 323, 326, 327 ganglion, 26, 154, 155, 251, 262 flora, ix, 92, 138, 153, 155, 342, 343, 344 gangliosides, 7 flow, 13, 34, 35, 65, 68, 82, 115, 122, 140, 153, 182, gastric, 83 285, 315, 325, 327, 329, 339 gastritis, 144 fluctuations, 32 gastroesophageal reflux, 37 fluid, 3, 50, 52, 54, 60, 61, 66, 110, 175, 183, 214, gastrointestinal, 20, 63, 170, 185, 225, 226, 227, 343 217, 221, 266, 357 gastrointestinal tract, 63, 170, 185, 225, 226, 343 fluorescence, 216 GCS, 301 fluorescence in situ hybridization, 216 gender, 36 fluoroscopy, 121, 272, 275, 289 gene, 7, 9, 15, 21, 34, 40, 199, 209, 216, 229 fMRI, 46, 71 gene expression, 9 focusing, 325 general anesthesia, 18, 125 folding, 172, 324 generation, 26, 69, 71, 76, 96, 180, 205, 238 follicle, 138, 139, 159, 160 genes, 9, 21, 36, 216, 224, 229 follicles, ix, xiii, xiv, 137, 138, 139, 141, 144, 147, genetic defect, 7 148, 150, 151, 153, 157, 158, 161, 164, 165, 331, genetic mutations, 34 332, 333, 335, 336, 337, 338, 339 genetic testing, 11, 15, 37 follicular, 139, 158, 159, 160, 338, 339, 340 genetics, 40 food, 8, 14, 22, 30, 46, 50, 51, 52, 53, 54, 58, 59, 60, Geneva, 212 64, 66, 68, 110, 150, 152, 170, 171, 172, 174, genome, 219 175, 176, 179, 181, 182, 183, 184, 186, 195, 205, genomics, 216 264, 265, 268, 271, 275, 300, 302, 354 Germany, 166, 202 food intake, 176, 179 germination, 160 foramen, 6, 7, 8, 12, 18, 23, 42, 164, 214, 224, 313 gingivitis, 65, 200 foramen ovale, 224 girls, 101, 223 formaldehyde, 332 gland, 72, 221 Fourier, 34 glass, 50, 146 Fox, 46 glasses, 16 374 Index glatiramer acetate, 16 half-life, 316 glioblastoma, 56 halitosis, 58 glioblastoma multiforme, 56 handicapped, xii, 263 gliomas, 41 handling, 175, 243 gliosis, 11 hands, 14, 15, 197, 325, 328 globus, 58 hanging, 70 glomerulonephritis, 141, 153, 157 hard tissues, 239 glossitis, 200 harvest, 324 glossopharyngeal nerve, 2, 23, 25, 26, 27, 44 harvesting, 324, 325, 326, 329 glottis, 31, 35, 181 head and neck cancer, viii, xii, 3, 8, 12, 39, 49, 56, glucose, 11, 30, 316, 320, 321 64, 70, 73, 77, 180, 184, 189, 190, 191, 236, 279, glucose metabolism, 30 280, 291, 298, 320 glutamate, 16, 31 head injuries, viii, 49 glutathione, 28, 354 head injury, 8, 114, 258, 307, 308 glutathione peroxidase, 354 head trauma, 74, 258, 259, 307, 308 glycerin, 145 headache, x, 25, 193, 197, 202, 213, 214, 220, 237, glycoprotein, 315 246 goals, 61, 62, 86, 117, 123, 182 healing, xii, 156, 238, 243, 244, 280, 324, 326, 327 gold, x, 22, 37, 43, 175, 193, 205, 237, 265 health, 16, 20, 53, 64, 73, 76, 80, 87, 97, 187, 358 gold standard, x, 22, 37, 43, 175, 193, 205, 237, 265 health care, 16, 76, 358 gonorrhea, 200, 209, 210 health care professionals, 16 grafting, 326 healthcare, 38, 245 grafts, xii, xiii, 280, 285, 291, 296, 323, 325, 329 hearing, viii, 25, 79, 80, 81, 84, 88, 89, 102, 115, gram negative, 201 118, 214 Gram-negative, 201 hearing impairment, 115 granules, 199 hearing loss, 25, 89, 102, 214 gravity, 68, 120, 181 heart, 3, 17, 83, 227 gray matter, 11 Heart, 246 Great Britain, 344 heart rate, 17 groups, xiii, 65, 69, 85, 93, 151, 152, 155, 172, 183, heat, 238, 243, 244 194, 195, 215, 223, 230, 300, 326, 331, 332, 337, height, 82, 83, 84, 93, 120, 160, 333 344 hemangioma, 173 growth, viii, 11, 38, 79, 80, 81, 82, 85, 86, 87, 88, hematocrit, 256 91, 92, 93, 97, 99, 100, 101, 104, 141, 205, 222, hematologic, 155 314, 326, 344 hematological, 5, 354 growth hormone, 91 hematoma, vii, xi, 8, 13, 249, 250, 251, 252, 253, GSM, 193 254, 255, 256, 257, 258, 259, 260, 261, 262, 280, guidance, 80 285 guidelines, 19, 41, 42, 167, 183, 194, 204, 209, 346 hematomas, 259, 260 Guillain-Barré syndrome, 3, 7, 11, 14, 17, 39, 40, hematopoietic, 226, 353 173 hematopoietic stem cell, 226 guilty, 156, 157 hematopoietic system, 353 gustatory, 188 hemianesthesia, 25 gynecomastia, 11 hemiparesis, 13, 24, 25, 68 gyrus, 23, 25 hemisphere, 32, 55, 177 hemoglobin, xiv, xv, 348, 352, 353 H Hemoglobin, 256, 352, 353 hemolytic anemia, 197 hemophilia, 251, 260 H2, 312 haemostasis, xi, 236, 242 hemorrhage, 10, 24, 26, 260, 261, 262

Index 375 hemorrhages, 7 Hungarian, 133 hemostasis, xi, 125, 235, 239, 243, 245, 255 Huntington‘s disease, 34, 60 hemostatic, xi, 235, 239 hybridization, 216, 219, 224, 230 hepatitis, 4, 39 hydration, 52, 53, 54, 62, 64, 67, 342 hepatomegaly, 196 hydrocephalus, 11 hepatosplenomegaly, 215, 257 hydrogen, 243 heredity, 163 hydrogen bonds, 243 Hermes, 45 hygiene, 145, 176, 358 herpes, x, 4, 26, 27, 45, 193, 194, 195, 208, 226 hyoid, 50, 51, 85, 92, 94, 174, 178, 179, 180, 264, herpes simplex, x, 4, 193, 194, 195, 208 267 herpes zoster, 26, 27, 45 hyperalgesia, 26 herpesviruses, 26 hypercapnia, 20, 237, 243 heterochromatin, 138 hyperkeratosis, 147 heterogeneity, 312 hyperplasia, 140, 141, 142, 143, 148, 157, 167, 195, heterogeneous, 39, 226, 285 339 high risk, xiv, 56, 181, 184, 215, 347, 348 hypersensitivity, 205 high-frequency, xi, 235, 275 hypertension, 16, 24, 37, 237, 246 high-level, 38 hypertrophy, xiii, 21, 94, 99, 105, 114, 139, 140, high-risk, 181 142, 143, 144, 147, 148, 149, 150, 152, 161, 162, hippocampus, 30 163, 165, 167, 168, 198, 236, 237, 243, 331, 332, Hippocrates, 357, 358 333, 334, 336, 339, 340 histologic type, 219, 226 hypesthesia, 24 histological, 166, 167, 219, 221, 225, 339 hypoglossal nerve, 171, 174, 214 histology, 143, 168, 219, 222, 313 hypoplasia, 85, 86, 87, 114, 221 HIV, 194, 198, 206, 208, 209, 226 hypopnea, 48, 96, 240, 242, 246, 247 HIV infection, 198, 208 hypopnoea syndrome, 48 HIV-1, 198, 208 hypotension, 25 HLA, 75 hypothalamus, 50 homeless, 358 hypothyroidism, 34, 221 Homocysteine, 355 hypotonia, 114 homogenous, 159 hypoxemia, 243 honey, 183 hypoxia, 17, 95, 237 hormone, 91 horse, xiii, 331, 332 I horses, 201 hospital, 62, 121, 191, 208, 245, 342, 359 IARC, 319 hospitalization, 289, 327 iatrogenic, xii, 3, 4, 6, 172, 263 hospitalized, 176, 345, 355 IBM, 9, 14, 20 host, 198, 202, 343 identification, 11, 13, 18, 33, 210, 265, 276, 314 House, 166 idiopathic, 5, 6, 8, 20, 21, 57, 74 households, 195 IgG, 7, 10, 27, 221, 338 HRP, xiii, 331, 332, 334, 335 ileum, 201 HSCT, 226 Illinois, 98 HSV-1, 198 images, 66, 85, 157, 265, 266, 267 human, viii, x, 73, 75, 79, 80, 83, 155, 166, 167, 171, imaging, vii, x, xiii, 3, 13, 34, 39, 41, 119, 180, 213, 186, 187, 188, 193, 194, 201, 208, 211, 227, 232, 215, 217, 228, 262, 265, 274, 275, 276, 296, 311, 298, 315, 320, 333, 339, 340, 357 313, 314, 315, 316, 317, 318, 320, 321, 329, 359 human immunodeficiency virus, 194, 208 imaging modalities, 317, 318 humans, 81, 191, 199, 201, 203, 237 imaging systems, vii, xiii, 311 humoral immunity, 338 imaging techniques, xiii, 311, 315 376 Index imbalances, 83, 89 incubation period, 195, 196, 197, 199, 202 imitation, 115 incurable, 314 immature cell, 139 independence, 62, 64 immobilization, xi, 249 India, 45, 319 immune function, 53, 185, 353 Indian, 39, 98, 361 immune globulin, 18 indication, 17, 154, 164, 181, 218, 240, 324 immune reaction, 332, 337 indicators, 273 immune response, ix, xiv, 7, 9, 53, 332, 338, 339 indices, xiv, 177, 348, 352, 354, 355 immune system, ix, 53, 55, 137, 176 indigenous, 4 immunity, 208, 226, 332 induction, 225, 226 immunization, 199 induction chemotherapy, 226 immunoassays, 199 induration, 314 immunocompetence, xv, 348, 353 ineffectiveness, 194 immunocompetent cells, 338 infants, 92, 185, 197, 276, 358 immunocompromised, 223, 345 infarction, 3, 15, 24, 72 immunocytochemistry, 339 infectious, x, 3, 6, 11, 146, 148, 152, 154, 155, 156, immunodeficiency, 194 157, 161, 163, 172, 173, 193, 202, 207, 208, 209, immunodeficient, 223 296, 340 immunoelectrophoresis, 227 infectious disease, 3, 6, 146, 148, 161, 172, 173, immunofluorescence, 27 207, 208, 209 immunoglobulin, 43, 223, 224, 227, 333, 342 infectious mononucleosis, 202, 207, 208, 340 immunohistochemical, xiii, 158, 166, 201, 215, 223, inflammation, xiv, xv, 26, 140, 141, 142, 143, 144, 331, 332 146, 155, 159, 165, 195, 215, 250, 264, 338, 339, immunohistochemistry, 143, 219 347, 348, 350, 352, 353, 354, 355, 358, 359 immunological, 6, 27, 167, 338, 339, 357 inflammatory, x, xiv, 4, 6, 7, 8, 14, 20, 26, 28, 40, immunology, 167 43, 60, 138, 140, 143, 145, 146, 147, 148, 153, immunoprecipitation, 199 156, 157, 158, 161, 173, 193, 194, 195, 199, 214, immunoreactivity, 229 295, 314, 332, 342, 343, 348, 350, 355, 360 immunosuppression, 226, 227 inflammatory bowel disease, 355 immunosuppressive, 20, 227 inflammatory cells, 199, 342 immunosuppressive agent, 20 inflammatory disease, 4 immunotherapy, 20 inflammatory mediators, 195 impairments, 2, 34, 50, 53, 59, 63, 64, 76, 189, 265, inflammatory response, xiv, 26, 195, 314, 332, 348, 267, 274, 300 350, 355 implants, 129 influenza, x, 193, 194, 195, 196, 358 implementation, 185, 186 influenza a, 358 impulsivity, 60 informed consent, 240 in situ, 28, 32, 224, 230 ingest, 61, 289, 293, 294 in situ hybridization, 216, 224, 230 ingestion, xi, 14, 174, 176, 202, 249, 261 in vitro, 200, 203, 339, 343 inguinal, 196 in vivo, 316, 340, 343 inhalation, 21, 68, 75, 359, 361 inactivation, 244 inheritance, 11, 15 inactive, 202 inhibition, 154 incidence, 3, 5, 18, 19, 22, 54, 56, 57, 60, 65, 73, 74, inhibitors, 19, 31, 32, 43, 46 113, 121, 186, 209, 223, 230, 232, 259, 282, 287, initial state, 265 297, 300, 305, 306, 307, 312, 313, 342, 346, 355 initiation, ix, 20, 22, 28, 52, 53, 54, 56, 59, 67, 70, inclusion, 6, 20, 26, 40, 60, 75 137, 171, 185, 199, 268, 289, 306 inclusion bodies, 26 injection, 23, 31, 35, 40, 44, 70, 71, 264, 271, 275 incompressible, 12 injections, 58, 60, 71, 77 incubation, 195, 196, 197, 199, 202, 333 injuries, 13, 43, 57, 59, 61, 63, 173, 258, 300, 358

Index 377 injury, 7, 8, 9, 19, 75, 114, 126, 173, 243, 244, 247, involution, 151, 161 249, 250, 252, 256, 257, 258, 259, 299, 300, 301, Iodine, 315 307, 308 ipsilateral, 3, 4, 11, 12, 13, 24, 181 inoculation, 198 Iran, 297 insertion, 126, 184, 294, 297 Ireland, 40 insight, 59, 60, 71 iridocyclitis, 156 insomnia, 37 iron, xiv, 347, 348, 349, 350, 351, 352, 354, 355 Inspection, x, 118, 193 irradiation, 218, 221, 291, 297, 320 inspiration, 36, 83, 88, 162, 237 irradiations, 151 instability, 10, 16, 30, 60, 296 irritability, 198 instruction, 178 irritation, xv, 144, 145, 165, 184, 357 instruments, 243, 244 IRS, 216, 217, 219, 228, 229 insulin resistance, 15 ischemia, 5, 28, 44, 291, 296 integration, 28 ischemic, 4, 13, 15, 41, 301 integrity, 29, 58, 61, 63, 174, 181 ischemic stroke, 41 intensive care unit, 17 island, 292, 330 interaction, 65, 72, 81, 85, 120, 338 isoforms, 26 interaction effects, 65 isolation, 4, 11, 21, 198, 199, 200 interactions, 65, 312 isoniazid, 18 interdependence, 340 Israel, 47, 232 interdisciplinary, 102 Italy, 235, 239, 263, 265 interferon, 16, 222, 332, 338 interferon-γ, 332, 338 J interleukin, 332, 338 interleukin-2, 332 JAMA, 166, 167, 206, 208, 212, 246 Internet, 41, 360 Japan, 190, 202, 211, 279, 344 interstitial, 14, 63 Japanese, 7, 11, 134 interstitial lung disease, 14, 63 Japanese encephalitis, 7, 11 interval, 15, 281, 314 jaw, 12, 26, 50, 61, 80, 81, 82, 85, 92, 99, 178, 185 intervention, ix, 17, 19, 31, 55, 56, 57, 71, 73, 97, jejunum, 281, 284, 289, 294, 295, 296 109, 114, 118, 123, 124, 125, 164, 186, 257, 307 joints, x, 14, 193 intervention strategies, 307 Jordan, 211 interview, 118 judgment, 34, 117 intoxication, 34 Jun, 73, 74, 75, 76, 77, 229, 230, 231, 232, 233, 277, intracerebral, 17, 24 297, 298, 308, 360, 361 intracerebral hemorrhage, 24 Jung, 187 intracranial, 7, 12, 17, 18, 24, 41, 217, 218, 220, 257 intracranial aneurysm, 7 K intracranial pressure, 12, 17, 41 intramuscular, 9, 14, 200 Kawasaki disease, 4 intraoperative, xi, 236, 242, 244, 248, 286, 289, 290, Kennedy‘s disease, 6, 7, 11, 17 293, 294, 295 keratosis, 143 intravascular, 18 kidneys, 226 intravenous, 18, 19, 28, 342, 345 kinase, 8, 9, 15, 40, 43, 233 intravenous antibiotics, 345 Korea, 169 intravenously, 16 Korean, 100, 187 invasive, 5, 16, 22, 38, 56, 123, 175, 217, 227, 238, Kosovo, 211 239, 253, 256 kyphosis, 83 inversion, 116 Investigations, 149 378 Index

L lift, 35, 124, 182 ligament, 25, 57, 250, 295 labeling, 216 likelihood, 59, 68, 204, 206, 345 laboratory studies, 208, 245 limb weakness, 15 lack of control, 59 limitation, 326 lactose, 201 limitations, 57, 66, 175, 245, 275 lambda, 336 linear, 10, 85, 333 lamina, 7 lingual, ix, 23, 31, 34, 76, 77, 82, 137, 147, 149, 164, laminar, 7 165, 288 language, ix, 17, 33, 74, 109, 118, 119, 121, 129, lipophilic, 315 133, 171, 190 liposuction, 327 Laryngeal, vi, 43, 65, 76, 117, 270, 271, 281, 323 liquids, 9, 30, 46, 51, 65, 68, 72, 176, 183, 191, 204, laryngeal cancer, 281, 286 266, 271 laryngectomy, 56, 239, 281, 290, 297 listening, 33, 67, 118 laryngitis, 4, 148, 150, 173, 252 liver, xiv, 144, 215, 220, 226, 227, 233, 256, 313, laryngoscope, 66 347, 348, 350, 354 laryngoscopy, 22, 66, 313, 359 liver cirrhosis, 256 laryngospasm, 264 liver failure, 144 larynx, xii, 9, 11, 12, 27, 31, 33, 35, 51, 56, 63, 66, liver metastases, 215 67, 68, 117, 147, 149, 151, 165, 173, 175, 178, liver transplant, 233 179, 180, 182, 185, 199, 263, 264, 265, 266, 268, liver transplantation, 233 270, 271, 272, 289, 320 loading, 177 laser, xi, 164, 235, 238, 239, 243, 244, 246, 247, 248 local anesthetic, 27 lasers, 238, 246 localised, 339, 359 latency, 10 localization, 6, 23, 114, 313, 333, 337, 338 late-onset, 40, 47, 227 location, 26, 54, 55, 56, 66, 119, 131, 141, 273, 288, lateral sclerosis, 6, 22, 31, 41, 42, 75, 114 301, 314 latex, 199, 209 locus, 223 latissimus dorsi, 281, 291 London, 42, 133, 232, 339 laughing, 9, 34 long period, 2, 70, 144 L-carnitine, 28 lordosis, 84 leakage, ix, 10, 19, 109, 182, 243, 268, 269, 289, low risk, 70, 128 293, 294 low tech, 132 leaks, 71 low temperatures, xi, 235, 239 learning, 11, 91, 185, 275 lower esophageal sphincter, 51 left hemisphere, 171 lower respiratory tract infection, 203 Legionella, 211 lumbar, 5, 11, 74, 224 Legionella pneumophila, 211 lumbar puncture, 5, 11, 224 lesions, xii, 2, 5, 6, 7, 8, 9, 10, 17, 18, 23, 24, 25, 33, lumen, 12, 13, 91, 252 34, 55, 57, 65, 125, 140, 146, 147, 153, 157, 161, luminal, ix, 137 164, 173, 197, 198, 199, 216, 224, 227, 228, 233, lung, 8, 14, 63, 144, 215, 313 243, 263, 299, 301, 303, 307, 308, 312 lung cancer, 8, 63 leukemia, 163, 225, 233 lung disease, 14, 63 leukocytes, 195, 207, 360 lung metastases, 215 leukocytosis, 12, 155, 163, 360 lungs, 51, 63, 65, 83, 217, 220 levator, 3, 21, 88, 110, 111, 114, 125, 126 lupus, 157 levodopa, 10, 16, 30, 31 lying, 68 Lewy bodies, 29, 30 lymph, x, xii, xiii, 193, 196, 198, 200, 201, 202, 204, lifestyle, 237 213, 214, 215, 217, 218, 219, 220, 221, 223, 224, life-threatening, vii, viii, 49, 95, 342, 358

Index 379

225, 226, 230, 250, 279, 280, 282, 290, 291, 297, malnutrition, vii, viii, xii, xiv, xv, 17, 49, 174, 176, 313, 314, 331, 332, 333, 335, 336, 337, 338, 339 263, 347, 348, 350, 352, 353 lymph node, x, xii, 193, 202, 204, 213, 214, 215, malocclusion, 15, 80, 84, 87, 92, 93, 97, 99, 100, 217, 218, 219, 220, 221, 223, 225, 226, 250, 279, 101, 102, 104, 116 280, 282, 290, 291, 297, 313, 314 management practices, 346 lymphadenectomy, 219 mandible, 81, 83, 84, 86, 92, 93, 95, 264, 301 lymphadenitis, 201 mandibular, 38, 81, 82, 83, 84, 85, 86, 92, 93, 94, 95, lymphadenopathy, 196, 198, 200, 201, 214, 215, 96, 97, 104, 106, 110, 221 217, 219, 224, 230, 313 manganese, 354 lymphangitis, 203 manipulation, 171 lymphatic, ix, 19, 82, 137, 139, 140, 142, 144, 148, manpower, 327 152, 153, 157, 160, 161, 164, 165, 313, 314, 333 mantle, 333, 334, 335, 337, 338 lymphatic system, 160, 161 marijuana, 358, 359, 361 lymphoblast, 138 marrow, 202, 217, 221, 222, 223, 225, 226 lymphocytes, ix, 137, 138, 139, 152, 153, 157, 159, Mars, 166 163, 226, 337, 338, 339, 340 mask, 38, 87, 100, 101, 115 lymphocytosis, 227 mast cell, 340 lymphoid, ix, 137, 138, 139, 143, 144, 147, 148, mastication, viii, 79, 80, 170, 174 149, 150, 151, 152, 157, 158, 161, 162, 164, 165, masticatory, 28, 214 195, 214, 223, 312 mastoid, 215 lymphoid follicles, ix, 137, 138, 144, 147, 150, 151, matrix, viii, 79, 81, 266, 329 157, 158, 161, 165 maturation, 139 lymphoid hyperplasia, 195 maxilla, 81, 84, 85, 86, 87, 89, 92, 94, 96, 100, 116, lymphoid tissue, 143, 145, 147, 148, 149, 150, 151, 118, 287 161, 162, 164 maxillary, vii, viii, ix, 44, 79, 81, 82, 83, 84, 85, 86, lymphoma, 214, 215, 222, 223, 224, 225, 227, 228, 87, 88, 89, 90, 91, 92, 94, 96, 98, 100, 101, 102, 230, 233 103, 104, 106, 109, 114, 219, 313 lymphomas, 223, 225, 226, 228, 231, 232, 233 maxillary sinus, 219 lysis, 15, 227, 233 McGillicuddy, 74 MDR, 315 M meals, 29, 31, 53, 63, 155 measurement, xii, 30, 121, 122, 247, 300, 305, 306 M1, 220 measures, 15, 17, 25, 28, 38, 118, 119, 121, 184, macrophages, 9, 14, 138, 159, 332, 337, 338 189, 309 magnetic, 3, 41, 119, 275, 313, 321 meat, 183 magnetic resonance, 3, 41, 71, 119, 171, 187, 275, mechanical ventilation, 186 313, 321 media, 11, 88, 89, 102, 149, 153, 165, 203, 242, 313 magnetic resonance imaging, 3, 41, 71, 119, 171, median, xiii, 111, 140, 215, 226, 227, 331, 333 187, 275, 313, 321 mediastinitis, 342 maintenance, 37, 218, 225 mediastinum, xi, 220, 249, 250, 252, 253, 254, 255 major histocompatibility complex, 9 mediation, 56, 61 maladaptive, 116 mediators, 195 malaise, 196, 198, 202, 203 medication, 60, 65, 198, 256 males, 9, 99, 240, 312 medications, x, 31, 35, 52, 61, 62, 64, 193, 198, 237 malignancy, 4, 20, 223 MEDLINE, 316 malignant, vii, x, xiii, 3, 8, 173, 213, 214, 215, 219, medulla, 2, 3, 7, 25, 33, 170, 172, 173 223, 226, 228, 291, 296, 311, 312, 315, 316, 320 medulla oblongata, 2, 170, 172, 173 malignant cells, 315 MEG, 171 malignant tumors, 8, 214, 215, 219, 291, 316 memory, 29, 30, 59 men, 15, 200, 209, 242, 301 380 Index meninges, 7 modality, 5, 13, 18, 218, 225, 319 meningioma, 7 modernization, 98 meningitis, 6, 7, 11, 42, 202, 211, 214 modulation, 2, 54, 218, 221 mental age, 121 modus operandi, 186 mental retardation, 115 molecular biology, 215, 224 Merck, 333 molecular mechanisms, 29 mesothelioma, 63 molecular mimicry, 34 meta-analysis, 37, 38, 47, 70, 77, 189, 236 molecules, 9, 243 metabolic, 34, 35, 176, 185, 315, 316, 319 molybdenum, 354 metabolic disorder, 34 monkeys, 100 metabolism, 30, 139 monoamine, 32 metastases, 18, 42, 215, 220, 221, 222, 228, 291, monoamine oxidase, 32 297, 314 monoclonal, 27, 224, 227, 233 metastasis, xii, 216, 217, 220, 279, 280, 282, 283, monoclonal antibody, 27, 227, 233 290, 291, 313, 314 mononuclear cells, 332, 339 metastasize, 313 mononucleosis, 196, 198, 207, 208, 226, 227 metastatic, xi, 55, 220, 230, 249, 251, 262 monozygotic twins, 93, 97 methylprednisolone, 16 Montenegro, 331 mice, 14 morbidity, xiii, 91, 199, 237, 238, 291, 300, 314, microbial, 157, 167, 338 323, 324, 325, 328, 330, 342 microclimate, 145, 148 morning, 144, 151 microflora, 104 morphological, xiii, 81, 83, 311, 337, 338 micronutrients, 354 morphology, 81, 82, 83, 84, 85, 91, 94, 97, 98, 99, microorganism, x, 193 102, 104, 105, 196, 327 microorganisms, 92, 194 mortality, 42, 61, 199, 226, 228, 230, 232, 237, 242, microscope, 147, 333 300, 314 microscopy, 15, 138, 200, 346 mortality rate, 228 microsurgery, 26, 291 mosquitoes, 201 microvascular, 28, 287, 289 motion, 9, 70, 112, 121, 124, 127, 128, 178, 185, 264 midbrain, 50 motor area, 28, 32, 54 Middle East, 357 motor control, 46, 59, 64 middle-aged, 76, 190 motor fiber, 2 migraine, 157 motor function, 3, 170, 177, 188 migration, 7, 184 motor neuron disease, 6, 7, 10, 42 military, 206, 207, 208 motor neurons, 2, 16, 32, 33 millet, 147 mouse, 14 mimicking, 3 mouth, viii, 37, 50, 51, 60, 61, 63, 79, 80, 81, 82, 83, mineralized, xi, 235, 244 84, 87, 88, 89, 91, 94, 96, 97, 98, 99, 124, 125, minerals, 176, 354 127, 148, 149, 162, 178, 185, 197, 198, 214, 240, miosis, 20 243, 264, 268, 324, 327, 343 mirror, 115, 119, 124, 177 movement, vii, ix, xi, xiii, 1, 2, 9, 21, 22, 28, 44, 50, misidentification, 238 51, 55, 57, 58, 61, 64, 65, 66, 67, 69, 71, 76, 80, Missouri, 320 85, 86, 92, 110, 111, 112, 117, 118, 120, 122, mitochondria, 315 130, 169, 171, 175, 177, 178, 180, 185, 186, 189, mitogen, 332, 338 235, 236, 239, 252, 263, 264, 265, 273, 275, 323, mitosis, 138, 139 324, 325 MMT, 219, 229 movement disorders, vii, 1, 2, 21, 44, 263 MMW, 166 MPA, 86 MND, 42, 59 modalities, 34, 189, 316, 317, 318

Index 381

MRI, xi, 3, 5, 10, 11, 12, 13, 22, 25, 44, 45, 119, Myotonic dystrophy, 9, 61 121, 133, 215, 216, 217, 220, 249, 255, 262, 295, 296, 313, 316, 317, 318 N mRNA, 211, 229, 340 MSI, 333 N-acety, 9, 40 mucosa, 29, 111, 125, 126, 127, 128, 144, 145, 146, nares, 119, 124, 204 147, 148, 150, 154, 163, 172, 195, 207, 215, 237, nasal cavity, 85, 90, 91, 103, 109, 110, 115, 220, 240, 241, 245, 248, 313 253, 256, 267, 311, 313 mucous membrane, 45, 195, 359 nasal polyp, 144 mucous membranes, 359 nasogastric tube, 184, 185, 191 mucus, 144, 175, 198 nasopharyngeal carcinoma, 3, 39, 219, 220, 228, mucus hypersecretion, 144 230, 231, 232, 233, 312, 313, 314, 316, 317, 319, multidimensional, 50 320, 321 multidisciplinary, viii, 16, 17, 49, 59, 61, 62, 67, 97, nasopharynx, 51, 63, 89, 120, 145, 146, 147, 173, 117, 132, 186, 259 175, 199, 214, 217, 219, 220, 221, 222, 224, 226, multiple sclerosis, 6, 10, 21, 24, 25, 41, 42, 114, 173 231, 265, 267, 312, 313, 314 multiplication, 138 natural, 2, 52, 73, 81, 91, 140, 172, 195, 207, 211, muscle biopsy, 15 267, 305, 307, 308 muscle contraction, 34, 61, 70, 146 natural evolution, 140 muscle mass, 191 nausea, 14, 203 muscle performance, 69 ND, 43, 131 muscle power, 13 neck cancer, 12, 56, 182, 184, 185, 282 muscle relaxant, 37 neck injury, 252, 256 muscle relaxation, 243 necrosis, xiii, 14, 17, 56, 245, 316, 326, 332, 339 muscle strength, 20, 30, 61, 179 necrotizing fasciitis, 203 muscle weakness, 14, 37, 59, 61 needle aspiration, 166, 346 muscles, x, 2, 3, 4, 9, 12, 13, 14, 15, 21, 32, 33, 36, negative consequences, 239 37, 50, 51, 52, 54, 55, 56, 58, 61, 68, 69, 70, 88, neocortex, 30 110, 111, 114, 123, 125, 126, 128, 130, 145, 151, neoformation, 148 175, 177, 178, 179, 180, 186, 193, 214, 215, 236, neonates, 214 237, 250, 263, 264, 292, 360 neoplasia, xii, 140, 164, 232, 263, 358 muscular dystrophy, 6, 9, 15, 22, 31, 40, 61, 75, 114 neoplasms, viii, x, 8, 34, 49, 63, 213, 320 musculoskeletal, 38, 189 Neoplasms, 55 mutation, 9, 15, 30, 41 neoplastic, 6, 8, 11, 12, 24, 312, 316 mutations, 7, 21, 34, 36 neoplastic diseases, 8, 24 myalgia, 198 nephritis, 150, 156, 157 myasthenia gravis, 6, 8, 13, 31, 35, 40, 43, 61, 75, nerve, 2, 3, 4, 6, 7, 8, 13, 14, 18, 20, 26, 27, 37, 40, 114, 173 56, 57, 70, 71, 130, 172, 195, 214, 238, 270, 290 Myasthenia Gravis, 61 nerve fibers, 6 myasthenic syndrome, 6, 8, 13, 20, 43 nerves, 2, 4, 7, 8, 10, 11, 18, 24, 33, 39, 41, 50, 51, Mycoplasma pneumoniae infection, 211 55, 57, 110, 114, 174, 214, 220, 263, 285, 324 myelin, 6, 36 nervous system, 2, 3, 23, 39, 41, 42, 72, 83, 228 myocardial infarction, 16, 237 network, 28, 32, 186, 313 myocarditis, 4, 199 neural mechanisms, vii, 1 myoclonus, 21, 33, 44 neural network, 28, 32, 50, 71 myoglobin, 216 neuralgia, 25, 26, 27, 45 myopathies, viii, 8, 43, 49, 60 neuroanatomy, 72, 171 myopathy, 6, 8, 14, 40, 173 neuroblastoma, 214 myositis, 20, 40, 60, 75 neurofibrillary tangles, 7, 10, 30 myotonic dystrophy, 6, 9, 15, 61, 114 neurogenic, 46, 114, 123, 124, 172, 173, 183, 276 382 Index neurological deficit, 26 nucleolus, 138 neurological disease, vii, viii, xii, 1, 2, 29, 30, 31, nucleus, 2, 3, 6, 7, 11, 23, 26, 28, 32, 54, 138, 139 34, 35, 36, 37, 38, 49, 263, 266 nucleus tractus solitarius, 28, 54 neurological disorder, 19, 22, 62 nursing, 64, 76, 264, 354, 355 neurologist, 62 nursing home, 76, 264, 354, 355 neuromuscular diseases, 172 nutrient, 291 neuronal cells, 29 nutrition, 52, 53, 54, 61, 62, 64, 67, 176, 183, 184, neuronal degeneration, 21 185, 265, 275, 307, 352, 354, 355 neuronal loss, 29 nutritional supplements, 64 neuronal migration, 7 nystagmus, 11, 12, 22, 25, 34, 44 neurons, 26, 29, 72 neuropathic pain, vii, 1, 23, 25 O neuropathy, 26, 36, 173 neurophysiology, 171 oat, 14 neurosurgeons, 57 obese, 37, 66 neurotoxic, 150 obesity, 36, 95, 236 neurotoxicity, 45 obligate, 80, 202, 344 neurotransmitter, 29 observations, 276, 343 New Jersey, 106, 301 obstruction, x, xii, 37, 57, 58, 59, 66, 80, 82, 83, 85, New York, 39, 40, 72, 74, 102, 131, 132, 186, 187, 87, 88, 94, 95, 97, 98, 100, 101, 104, 115, 116, 188, 190, 191, 206, 207, 319, 320 122, 127, 140, 141, 144, 148, 149, 150, 154, 161, Newton, 229, 261 184, 197, 199, 213, 214, 236, 237, 243, 250, 254, NHL, x, 213, 214, 222, 223, 225, 226, 227 258, 259, 260, 261, 262, 263, 268, 273, 313, 361 Nielsen, 209 obstructive sleep apnea, viii, 1, 35, 47, 48, 89, 94, NIH, 208 95, 96, 102, 104, 105, 106, 107, 245, 246, 247 Nile, 7, 11 Obstructive Sleep Apnea, 36, 236 NINDS, 41 obstructive sleep apnoea, 47, 48, 104, 105, 246 nitrate, 145 occlusion, 7, 14, 83, 88, 98, 99, 236 nitric oxide, 168 oculomotor, 7 NMDA, 31 oculopharyngeal muscular dystrophy, 6, 15, 31, 46 N-methyl-D-aspartate, 31 odds ratio, 271 nociceptive, 26 odynophagia, 197, 238, 250, 252 nodes, 19, 140, 203, 204, 215, 217 oedema, 358 nodules, 117 older adults, 76, 190, 196 noise, 236, 245 older people, 46, 183, 191, 312 non invasive, 253 olfactory, 50, 170 non-Hodgkin lymphoma, 228 oligomerization, 29 non-Hodgkin‘s lymphoma, 215, 222, 225, 227 oligospermia, 11 non-invasive, 38, 67, 69, 118, 121, 256 olive, 21, 22 normal children, 82 oncogene, 226 normal development, viii, 79, 80 oncological, 315 normalization, 305, 306 oncology, 229, 315, 316 North Africa, 219, 312 Oncology, 191, 215, 228, 229, 230, 232, 320, 321 North America, 218 online, 231 North Carolina, 207 operator, 275 nose, x, 4, 10, 14, 82, 87, 88, 91, 110, 115, 117, 118, ophthalmic, 157 120, 124, 127, 132, 149, 197, 213, 214 ophthalmoplegia, 15 nuclear, xiii, 7, 8, 15, 197, 230, 233, 311, 312, 315, optical, xiii, 247, 331, 333, 336, 337 316, 333 optical density, xiii, 331, 333, 336, 337 nuclei, 2, 7, 14, 33

Index 383 oral cavity, xii, 50, 51, 52, 56, 61, 65, 109, 110, 114, paralysis, vii, 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 14, 15, 20, 116, 170, 173, 174, 175, 176, 179, 240, 256, 263, 24, 25, 27, 33, 36, 39, 40, 41, 45, 54, 59, 114, 264, 268, 300 173, 259 oral health, 76 paramagnetic, 255 oral hygiene, 176, 358 parameter, 42, 272, 273, 275 oral stage, 50, 52 paraneoplastic, 34, 215 orbit, 220, 287 paraneoplastic syndrome, 34, 215 organ, viii, 79, 80, 145, 156, 223, 226, 227, 233, parathyroid, 251, 257, 261, 262 250, 308, 316, 357, 359 parenchyma, 142, 160 organic, 115, 154 parenteral, 5, 184, 185, 275, 345 organism, 5, 139, 199, 200, 201, 202, 205, 359 parents, 85, 94, 149 orientation, 114, 126 paresthesias, 25, 155 oropharyngeal region, 267 parietal lobe, 28 oropharynx, 22, 50, 51, 63, 92, 97, 140, 144, 173, Paris, 166, 167, 213, 230 175, 176, 199, 202, 214, 220, 226, 238, 264, 266, Parkinson disease, 21, 29, 32, 46, 72, 114 267, 268, 313 Parkinson‘s, 16, 46, 53, 55, 60, 63, 70, 263 orthodontists, viii, 79, 80, 87, 90 parkinsonism, 16, 30 orthopaedic, 57 Parkinsonism, 44 orthopnea, 252 parotid, 6, 8, 19, 221, 290 OSA, 35, 36, 37, 38, 81, 94, 95, 96, 97, 105 partial thromboplastin time, 251, 255 oscillations, 21 particles, 88 ossicles, 150 partnership, 50 osteoarthropathy, 215, 228 passive, 69, 115, 199, 209 osteomyelitis, 157, 296 pathogenesis, 4, 40, 46, 166, 195, 207, 208 otitis media, 88, 89, 102, 149, 153, 165, 313 pathogenic, ix, 53, 92, 138, 143, 152, 155, 160, 176, otolaryngologist, ix, 109, 117, 123, 129, 132 332 otorrhea, 150, 165 pathogenic agents, ix, 138, 143, 152, 332 outpatient, 238, 342, 346 pathogens, ix, 137, 176, 202, 343, 345 oxidative, 26, 45 pathologist, ix, 63, 64, 66, 109, 129 oxidative stress, 26, 45 pathology, 40, 140, 143, 144, 146, 148, 153, 156, oxygen, 63, 156, 237, 256, 291 164, 208, 258, 281 oxygen saturation, 63, 237 pathophysiological mechanisms, 300 oxyhemoglobin, 94 pathophysiology, vii, ix, 1, 2, 21, 29, 33, 38, 58, 96, 169, 170, 179, 182, 186 P pathways, 2, 29, 33, 36, 54, 150, 152, 165, 170, 263 patient care, 16 p53, 226 patient management, 346 Pacific Islanders, 200 PCR, 11, 27, 198, 199, 201, 202, 203, 209, 216, 340 pacing, 18, 35 pectoralis major, xii, 280, 281, 285, 286, 291, 292, packets, 8 293, 294, 295, 296 Paget‘s disease, 25 pediatric, 3, 38, 48, 97, 215, 218, 219, 220, 221, 229, pain, vii, x, xi, 1, 11, 12, 13, 17, 23, 24, 25, 26, 27, 232, 233, 308, 342 38, 57, 58, 65, 114, 115, 151, 155, 165, 189, 193, pediatric patients, 97, 220, 308 195, 201, 202, 203, 204, 215, 221, 236, 238, 240, pediatrician, 97, 123 242, 243, 244, 245, 252, 276 pelvis, 224 Pakistan, 311 penicillin, xiv, 5, 18, 35, 200, 205, 341, 343, 344, palliative, 17, 59 345, 359 palpation, 27, 118, 149, 155, 214, 313 Pennsylvania, 130, 131 pandemic, 208 perception, 74 paraffin-embedded, 230 perceptions, 110 384 Index perfusion, 275, 315, 325 plaque, 176 pericarditis, 156 plasma, 18, 198, 257, 338 perinatal, 118 plasma cells, 338 periodic, 9, 61, 316 plastic, 123, 280 periodontal disease, 65, 83, 341 plasticity, 55, 72, 73, 188 peripheral blood, 339, 340 platelet, 251, 255, 257 peripheral blood mononuclear cell, 339 platelet count, 255 peripheral nervous system, 62, 263 platinum, 26 peripheral neuropathy, 45, 173 play, 81, 139, 152, 164, 171, 223, 236, 238 peristalsis, 51, 272, 273 plexus, 2, 23, 110, 111, 156 peritoneal, 184 ploidy, 216 peritonsillar abscess, vii, xiv, 341, 342, 343, 344, pneumonia, 29, 58, 174, 271, 277, 300, 307, 308, 345, 346 348, 355 periventricular, 10 pneumonitis, 76 permeability, 149, 332 Poland, 341 permit, 11, 120, 314, 324 poliovirus, 7 person-to-person contact, 196 pollutants, 88 PET, xiii, 30, 71, 311, 316, 318, 319, 320, 321 pollution, 144 P-glycoprotein, 315 polycythemia, 237, 251 pH, 333 polymerase chain reaction, 11, 199, 211 phagocytosis, 338 polymorphism, 155 pharmacological treatment, 45 polymorphonuclear, 207 pharyngeal airway, 82, 85, 91, 92, 93, 94, 104 polymyositis, 6, 8, 20, 60, 173 pharyngitis, x, 143, 144, 145, 151, 165, 166, 167, polyp, 214 172, 173, 193, 194, 195, 196, 198, 200, 201, 202, polyps, 85 203, 204, 205, 206, 210, 212, 358 polysomnography, 37 phenotypes, 36, 229 pons, 2, 24, 173 phenotypic, 75, 216 pools, 196 phenytoin, 21 poor, 14, 19, 53, 57, 58, 59, 61, 88, 125, 152, 184, Philadelphia, 19, 39, 45, 98, 100, 104, 130, 131, 132, 216, 219, 221, 222, 228, 237, 324, 325, 327, 348, 186, 188, 189, 207, 208, 209, 319 358 phonation, 4, 9, 21, 22, 33, 35, 120, 149, 165, 266 population, 3, 59, 60, 92, 98, 99, 117, 138, 139, 179, phonemes, 115, 124 184, 195, 199, 201, 206, 216, 242, 300, 338, 342 photon, 316, 319, 320, 321 ports, 127 photophobia, 204 positron, 30, 71, 171, 316, 319, 321 physical therapy, 15, 17, 25, 70, 72 positron emission tomography, 30, 171, 319, 321 physicians, viii, 1, 38, 140, 205, 275, 359 postoperative, xii, 5, 71, 123, 127, 216, 217, 238, Physicians, 45, 64, 204 240, 243, 244, 245, 246, 279, 280, 281, 282, 285, physiological, ix, 37, 44, 69, 91, 110, 137, 181, 264, 289, 290, 291 265, 267, 332, 350 post-streptococcal glomerulonephritis, 203 physiology, xiii, 63, 64, 65, 67, 69, 70, 72, 77, 171, post-stroke, 73, 309, 355 186, 300, 303, 306 postsynaptic, 8 physiopathology, 45 post-transplant lymphoproliferative disorders, 227, physiotherapy, 16 233 pig, 248 postural hypotension, 42 pilot study, 46, 73, 100, 101, 102 postural instability, 10, 30, 60 pituitary, 91 posture, 2, 10, 25, 30, 63, 67, 68, 82, 83, 95, 96, 99, placebo, 20, 95 105, 179, 181, 182, 190, 277 planning, ix, 28, 98, 109, 123, 132, 174, 175, 187, potassium, 20, 199, 316 215, 231, 265, 285 potatoes, 183

Index 385 powder, 144 protection, 51, 54, 56, 57, 65, 67, 68, 71, 180, 181 power, 13, 238, 243, 244, 248, 301 protective mechanisms, 56, 74 PPP, 131 protein, xiv, 3, 7, 8, 15, 21, 29, 30, 176, 183, 191, prediction, 204, 212 233, 239, 243, 332, 338, 347, 348, 349, 350, 352, predictors, xiv, 30, 57, 76, 308, 309, 348, 352, 353 354 predisposing factors, 85, 88, 291, 297 proteins, 8, 9, 15, 36, 226, 350 preference, 37, 55 proteoglycans, xi, 235 prefrontal cortex, 32 prothrombin, 251, 255 pregnant, 200 protocol, 118, 157, 175, 177, 178, 185, 218, 233, pregnant women, 200 260, 265, 267, 346 preschool, 105, 195 protocols, 72, 174, 177, 181, 185, 216, 218, 222, preschool children, 105, 195 225, 227, 229 press, 132, 155 proto-oncogene, 223 pressure, xi, xiii, 7, 12, 15, 16, 17, 25, 30, 36, 37, 38, provocation, 175, 207 41, 48, 58, 69, 76, 82, 89, 95, 105, 115, 116, 119, pruritus, 140 122, 165, 172, 178, 180, 181, 182, 190, 235, 236, pseudo, ix, 137 237, 243, 246, 265, 272, 273, 275, 323, 325, 326, pseudobulbar palsy, 9, 10, 33 328, 329, 330, 333, 353, 354 PSP, 10, 16 pressure sore, 354 psychologist, 123 presynaptic, 6, 8, 20 psychoses, 64 prevention, 15, 38, 72, 74, 131, 200, 209, 256 psychosocial development, 17, 86 preventive, 25 ptosis, 13, 15 primary care, 167 PTT, xii, 299, 302, 303, 304, 305, 306 primary follicles, 139 puberty, 147, 148 primary school, 104 public health, 20 primary tumor, 5, 19, 313, 314 pulmonary circulation, 237 priming, 29 pulmonary embolism, 19 prior knowledge, 50 pulmonary hypertension, 237 probability, 149, 345 pulse, 17, 30, 104, 175 probe, 219, 224, 265 pumping, 315 production, xiii, 8, 29, 33, 55, 110, 114, 115, 116, puncture wounds, 59 119, 120, 122, 124, 131, 139, 176, 185, 199, 200, pupils, 14, 20, 163 223, 244, 331, 332, 337, 338, 339, 340, 360 purpura, 157 prognosis, 19, 62, 73, 216, 219, 221, 222, 225, 226, pus, xiv, 341, 343, 344, 345, 346 227, 307, 314 pylorus, 184 prognostic factors, vii, x, 73, 213, 222, 307 pyramidal, 10, 263 prognostic value, 216 program, 54, 70, 122, 204, 265, 333 Q programming, 46, 56 progressive supranuclear palsy, 6, 10, 41 QOL, 191 proinflammatory, 332 quadriceps, 14, 179, 189 proliferation, 17, 146, 157, 159, 168, 214, 223, 224, quality control, 339 226, 316 quality of life, xii, 16, 38, 50, 54, 57, 62, 63, 179, prophylactic, 28 182, 184, 242, 245, 279, 289 prophylaxis, 35, 225 questionnaire, 37, 190 propulsion, 51, 53 questionnaires, 239 prostheses, 190 prosthesis, 16, 35, 124, 182 R prosthetics, ix, 109, 130 prostrate, 8 race, xiv, xv, 347, 348, 349, 352, 353 386 Index radiation, xii, 17, 18, 19, 55, 56, 66, 120, 121, 173, regression analysis, 352, 353 175, 180, 184, 185, 191, 221, 253, 280, 281, 284, regular, 169, 183, 253 285, 291, 292, 293, 294, 295, 296, 314, 315, 320 regulation, 29, 32, 122 Radiation, 55, 57, 230, 281, 292, 314, 319, 321 regulators, 332 radiation damage, 56 rehabilitate, 71 radiation therapy, 17, 19, 180, 185, 296, 298, 314 rehabilitation, x, 5, 15, 25, 30, 34, 55, 57, 65, 67, 69, radio, 56, 65, 239, 319, 325 70, 73, 77, 169, 176, 177, 178, 184, 186, 188, radiofrequency, 238, 243, 247 191, 265, 300, 301, 307, 308 radiography, 119 rehabilitation program, 55, 70, 177, 265 radiological, 5, 71, 265, 267, 271, 272, 275, 315 reinforcement, 238 radiologists, 314, 64 relapse, 16, 154, 218, 221, 293, 294, 296 radionuclides, 315, 316 relapses, 41 radiopharmaceutical, xiii, 311, 315, 316, 319 relationship, viii, 79, 80, 82, 85, 87, 88, 89, 92, 93, radiotherapy, xii, 5, 18, 56, 189, 215, 218, 221, 222, 98, 102, 104, 117, 130, 156, 236, 246, 262, 273, 228, 231, 232, 279, 280, 281, 284, 291, 292, 294, 297, 313, 349, 352 297, 298, 313, 320, 321 relationships, viii, 75, 79, 80, 85, 86, 88, 92 Radiotherapy, 213, 218, 221, 225, 227, 230, 283, relaxation, 15, 22, 35, 51, 52, 58, 59, 60, 65, 69, 243, 291, 298, 320, 321 273, 274, 301 radius, xi, 235, 240 reliability, 175, 191, 280, 296 rain, 17 Reliability, 76, 133 random, 34, 286 REM, 237 range, xii, 17, 26, 35, 70, 72, 113, 117, 130, 175, remediation, 71, 114, 116, 132 183, 185, 201, 227, 263, 301, 306 remission, 225, 226, 227 raphe, 4, 111 remodeling, 81 rash, 14, 196, 197, 198, 201, 210 renal, 4, 157 rating scale, 308 repair, ix, 71, 77, 109, 113, 125, 126, 127, 134, 226, reading, 33 257, 258, 290 real time, 65, 121, 266, 267 repetitions, 33, 178, 185 reality, 50 replication, 198 reasoning, 170 resection, xii, 5, 16, 18, 19, 56, 74, 173, 182, 217, rebel, 152 218, 225, 279, 280, 281, 297, 313, 320, 328 receptors, 8, 36, 166, 245, 315 reservoir, 341 recognition, 8, 15, 25 residual disease, 217 reconstruction, xii, xiii, 124, 173, 279, 280, 285, residuals, 143, 149, 151, 152, 153 287, 290, 291, 292, 294, 296, 297, 298, 320, 323, residues, 9 324, 326, 327, 328, 329, 330 resin, 359 reconstructive surgery, 296, 360 resistance, xiv, 15, 31, 81, 88, 91, 96, 101, 103, 115, recovery, xi, 15, 16, 31, 35, 55, 71, 174, 177, 186, 141, 178, 201, 237, 315, 341 199, 236, 242, 245, 246, 306, 307, 308, 343 resistence, 152 rectus abdominis, 290 resolution, 57, 96, 121, 265, 267, 301, 308 recurrence, xiii, 5, 17, 138, 216, 221, 222, 227, 296, respiration, viii, 36, 50, 51, 59, 60, 67, 68, 79, 80, 297, 311, 314, 342 83, 88, 91, 97, 98, 99, 100, 101, 119, 150, 170, reflex action, 154 252, 271 reflexes, 9, 72, 91, 149, 355 respirator, 17 refractoriness, 19 respiratory disorders, 150 refractory, 20, 27 respiratory failure, 17, 59, 148, 162 regeneration, 14, 20 respiratory problems, 91, 96, 97 regional, 140, 175, 215, 217, 221, 224, 225, 232, respiratory syncytial virus, x, 193, 194 313, 314, 358, 361 responsiveness, 36, 45 regression, xiii, 218, 227, 311, 352, 353 retardation, 86

Index 387 retention, 51, 57, 59, 151, 152, 153, 154, 155, 157, satisfaction, 245, 247 268, 269, 272, 274, 276, 315 saturation, 237 reticulum, 138 sauna, 361 retrovirus, 208 scalp, 287 returns, 197 Scandinavia, 344 revascularization, 15 scar tissue, 91, 238 Reynolds, 207 school, 99, 104, 148, 203, 205, 206, 211 RFS, 221 Schwann cells, 8 rheology, 183 sclerosis, 6, 41, 146, 173 rheumatic, 34, 203, 205 scoliosis, 83 rheumatic fever, 34, 203, 205 scores, 20, 121, 133, 245 rheumatoid arthritis, 7, 18, 260 scotoma, 13 rhinitis, 88, 140, 144, 145, 147, 148, 150, 196, 207 scull, 287 rhinorrhea, 196, 203, 204 search, 14, 316 rhinovirus infection, 195, 197 secretion, 66, 144, 146, 154, 175, 338 rhythm, 83 sedatives, 37, 236 rhythmicity, 12 selenium, 355 ribonucleic acid, 8 semantic, 118 ribosomes, 138 senescence, 145 rice, 183 senile, 30 rigidity, 10, 30, 33, 60 senile plaques, 30 rings, 333 sensation, vii, xii, 1, 2, 23, 24, 27, 28, 29, 35, 36, 58, risk factors, 15, 74, 94, 291, 307, 352 61, 66, 144, 146, 151, 155, 162, 165, 263, 358 risk profile, 18 sensations, xiii, 144, 145, 147, 155, 323 risks, 60, 238 sensitivity, 19, 20, 30, 53, 66, 67, 152, 174, 175, rituximab, 227, 233 205, 264, 317, 318, 319, 337, 343 Rituximab, 233 sensorimotor cortex, 32, 171 RNA, 8, 198, 230 sensors, 275 room temperature, 333 sentences, 124 rotations, 30 separation, 34 rubber, 127, 128 sepsis, 12, 342 Russian, 209 septicemia, 155, 156, 157, 201, 210 septum, 116, 118, 144, 150 S sequelae, xiii, 204, 218, 221, 222, 323, 325 sequencing, 60, 271 saccades, 10 Serbia, 331 safety, 23, 31, 38, 66, 172, 176, 183, 184, 187, 205, series, xiii, 59, 124, 131, 220, 221, 222, 266, 323, 218, 227, 239, 243 326, 358 saline, 145, 332 serologic test, 196, 201 saliva, 16, 27, 31, 49, 50, 52, 53, 54, 55, 65, 171, serology, 5, 221, 319 176, 177, 186, 195, 198, 204, 268, 357 serum, xiv, xv, 4, 11, 14, 18, 27, 145, 221, 339, 340, salivary glands, 31, 55, 221 347, 348, 349, 350, 351, 352, 353, 354 salt, 50, 219 serum albumin, 348, 350 sample, 14, 85, 118, 122, 129, 199, 209, 215, 333 severity, 5, 30, 37, 54, 55, 56, 95, 114, 175, 198, saprophyte, ix, 138, 152, 153 199, 236, 238, 300, 301 sarcoidosis, 7, 18 sex, 200, 209, 223, 281 sarcomas, 228, 229 sex ratio, 223 SARS, 122, 123 sexual contact, 200 SAS, 166 Sexually transmitted diseases, 42, 209 satellite, 163 Sexually Transmitted Infections, 42 388 Index shape, 35, 81, 118, 119, 267, 287, 324 social life, 110 shares, 129, 315, 319 sociopsychological, 170 sheep, 199, 201, 210 sodium, 26, 316 shock, 227 soft palate, viii, x, 4, 9, 11, 12, 21, 24, 38, 50, 51, 52, short period, 82, 305 68, 82, 95, 109, 110, 111, 114, 118, 119, 124, shortness of breath, 27 125, 127, 128, 175, 182, 186, 197, 198, 203, 235, short-term, 18, 20, 67, 87, 184, 186 236, 237, 238, 239, 240, 241, 247, 264, 266, 311 Short-term, 134 soft tissue sarcomas, 228 shoulder, 11, 292 soft tissue tumors, 215 shoulders, 14 software, 122, 265 sialic acid, 9 solid state, 265, 266, 275, 277 sibling, 99, 204 Solow, 101, 105 side effects, xi, 16, 18, 35, 235, 238, 245 somatosensory, 177, 188 signs, 3, 4, 6, 9, 10, 11, 12, 15, 22, 25, 29, 55, 60, 63, somnolence, 242 66, 149, 155, 174, 198, 204, 215, 217, 221, 226, sores, 354 227, 313, 333, 338 sounds, 33, 34, 46, 67, 115, 124, 179, 236, 357 silicon, 83, 354 South Africa, 360 silver, 145 South Pacific, 200 similarity, 35 Soviet Union, 208 sine, 275 Spain, 299, 301 Singapore, 41 spastic, 12, 31, 33, 144, 145 sinuses, 215, 217, 268, 301 spasticity, 16 sinusitis, 140, 150, 151, 153 spatial, 10, 81, 169, 181 sites, xi, 125, 129, 194, 200, 215, 216, 218, 220, 222, specialized cells, ix, 137 225, 236, 237, 242, 243, 314, 324, 327, 329, 337 species, 205, 343, 344 skeletal muscle, 15, 191 specificity, 30, 66, 174, 175, 317, 318, 319, 333, 337 skeleton, viii, 79, 80, 81, 82, 83, 89, 98, 99, 102 SPECT, 316, 317, 318, 320, 321 skills, viii, 49, 62, 64, 67, 243 spectrum, xiv, 40, 201, 205, 209, 228, 341, 345 skin, xiii, 4, 14, 20, 27, 69, 70, 148, 176, 199, 200, speech, vii, viii, ix, 1, 2, 5, 15, 16, 17, 32, 33, 34, 35, 221, 238, 280, 284, 285, 286, 290, 291, 292, 294, 46, 47, 50, 63, 66, 74, 75, 79, 80, 91, 109, 110, 296, 297, 298, 323, 324, 325, 326, 327, 328, 329, 111, 114, 115, 116, 117, 118, 119, 120, 121, 123, 330 124, 129, 130, 131, 132, 133, 134, 182, 190, 226, skull fracture, 6, 257 328, 357, 360 SLE, 173 speech sounds, 124 sleep, viii, ix, x, 1, 22, 35, 36, 37, 47, 48, 49, 53, 63, speed, 177, 185, 240, 243, 267 72, 81, 89, 94, 95, 96, 100, 102, 104, 105, 106, sphincter, 31, 46, 51, 52, 58, 59, 66, 71, 75, 76, 77, 107, 109, 114, 127, 148, 150, 164, 167, 235, 237, 119, 125, 130, 131, 135, 172, 178, 188, 190, 267, 238, 239, 243, 245, 246, 247, 358 276, 301, 341 sleep apnea, ix, x, 94, 95, 100, 106, 109, 114, 127, spices, 144 164, 235, 238, 239, 246 spinal and bulbar muscular atrophy, 41 sleep disorders, 47 spinal cord, 7, 8, 59, 173 sleep-disordered breathing, 81, 94, 96, 105, 237, spinal trigeminal tract, 23, 24, 26 246, 247 spindle, 216 smoke, xv, 314, 357, 359 spine, xi, 13, 57, 58, 74, 84, 110, 249, 250, 252, 256, smoking, xv, 16, 144, 341, 357, 358, 359 258, 259, 262, 295 smoking cessation, 16 spleen, 197 snoring, x, xi, 37, 47, 94, 95, 104, 105, 106, 114, splenic rupture, 197 127, 226, 235, 236, 237, 238, 239, 240, 242, 243, splenomegaly, 256 245, 246, 247, 358 splint, 106 social change, 237 spontaneous recovery, 55, 71

Index 389 sporadic, 4, 9 substances, 53, 139, 315 sports, 145, 147, 197 substantia nigra, 2, 29 SPT, 21, 22 substitutes, 243 sputum, 202 substrates, 71 squamous cell carcinoma, 3, 290, 292, 294, 298 success rate, 95, 325, 327 St. Louis, 98, 132, 258 successive approximations, 124 stability, 104 suffering, 92, 266, 271 stabilization, 19 sugar, 9, 50 stabilize, 3, 22 sulphate, 266 stages, 50, 101, 114, 146, 152, 169, 171, 196, 255, sumatriptan, 22, 44 264, 276, 313 summer, 50, 194, 196, 197, 207 standard deviation, 333, 336 Sun, 208 Standards, 42, 47, 229 superior vena cava, 19 Staphylococcus aureus, 92, 344 supervision, 80, 275 starch, 183 supply, 63, 130, 176, 185, 291, 324, 325 stasis, ix, 137 suppression, 26, 51, 145 STD, 209 surgeons, 57, 64, 113, 114, 127, 128, 280, 313 steel, 243, 248 surgeries, 290 stenosis, 16, 165 Surgery, 27, 48, 56, 130, 132, 133, 134, 166, 221, stent, 19 225, 239, 246, 247, 291, 292, 314, 320, 323, 361 sterile, 215 surgical intervention, 17, 19, 31, 56, 57, 114, 125, sternocleidomastoid, 12 139, 164, 173 steroids, 18, 19, 28, 342 surgical resection, 5, 173, 182 stethoscope, 67 surveillance, 41 stiffness, 221, 252 survival, 5, 16, 17, 219, 221, 222, 230, 232, 313, 314 stimulus, 14, 172 survival rate, 5, 232, 313 stomach, 50, 51, 60, 68, 172, 267, 300 survivors, 182 stomatitis, 65, 173, 197 susceptibility, 9, 73, 201, 210 strain, 4, 237, 251 suture, 89, 90, 102, 103 strains, 3, 205, 207, 209 swelling, x, xi, 4, 7, 12, 13, 57, 151, 204, 213, 249, strategies, x, 30, 40, 66, 67, 131, 169, 186, 204, 247, 255, 256, 258, 358 252, 307 switching, 82 strength, 20, 30, 53, 61, 69, 70, 179, 189, 243, 273 symmetry, 118, 120 streptavidin, xiii, 331, 332 symptom, 13, 52, 62, 148, 150, 151, 153 streptococci, 155, 156, 194, 201, 204, 205, 206, 212, symptomatic treatment, 5, 15, 16, 20, 31, 35, 38, 196 343, 344 synapse, 23 stress, 9, 13, 22, 26, 45, 343 synapses, 20 stretching, 185 synchronous, 324 striatum, 2 syndrome, x, 3, 6, 7, 9, 11, 12, 14, 17, 18, 20, 22, 23, stridor, xi, 4, 203, 249 24, 25, 26, 27, 29, 34, 39, 40, 41, 42, 43, 44, 45, stroma, ix, 137, 138, 142, 143 48, 54, 72, 85, 100, 102, 104, 105, 106, 107, 114, structural changes, 63, 85 140, 150, 151, 152, 157, 164, 173, 194, 196, 198, structural defect, 125 203, 227, 233, 235, 239, 246, 247, 259, 267 students, 194, 198, 206, 207, 208 synergistic effect, 182 subacute, 14, 155, 157, 255 synovitis, 215 subarachnoid hemorrhage, 354 syntactic, 118 subcortical structures, 50 synthesis, xiv, xv, 340, 347, 348, 350, 353, 354 subgroups, 284, 285 syphilis, 7, 18, 42 subjective, ix, 38, 109, 129, 151, 154, 189, 245, 273 syringomyelia, 12 submucosa, 150, 313 390 Index

T 213, 235, 236, 238, 239, 249, 250, 252, 258, 343, 345, 357, 358, 359, 361 T cells, 9, 14, 158, 159, 339 thrombocytopenia, 197 T lymphocyte, ix, 137, 138, 139, 158, 224, 226, 332, thromboembolic, 19 337, 338 thromboembolism, 185 Taiwan, 208, 261, 323 thrombolytic agents, 15 tardive dyskinesia, 64 thrombosis, 6, 7, 8, 12, 19, 40, 41 task force, 41, 44 thrombotic, 251 taste, 12, 24, 61, 66, 239 thrush, 198 tau, 7, 30 thymidine, 233 TBI, xii, xiii, 299, 300, 301, 302, 304, 305, 306 thymoma, 20 team members, 62 thymus, 149 technetium, 221, 320, 321 thyroid, 26, 57, 74, 111, 174, 248, 340 Technology Assessment, 44 thyroid gland, 340 teeth, viii, 15, 79, 80, 92, 95, 97, 98, 118, 124, 149 ticks, 201 Teflon, 71, 129 tight junction, 167 telangiectasia, 226 time periods, 91 telephone, 180 timing, 16, 32, 70, 103, 117, 273 television, 119 tinnitus, 13 temperature, 11, 25, 36, 54, 145, 146, 201, 247, 333 TNF, xiii, xiv, 331, 332, 333, 335, 336, 337, 338 temporal, xii, 5, 10, 30, 151, 169, 180, 300, 303, tobacco, 144, 359 304, 305, 306 toddlers, 197 temporal lobe, 30 Tokyo, 104 tendon, xiii, 110, 323, 324, 325, 326, 327, 330 tolerance, 63, 197, 221 tendons, 324, 326 Toll-like, 166 tensile, 243 tomato, 183 tensile strength, 243 Tongue, 69, 178, 268 tension, xi, 236, 240, 243, 257 tonic, 52 teratomas, 214 Tonsillar, 332, 333, 334, 340 territory, xii, 24, 25, 224, 300, 301, 303, 304, 306 tonsillectomy, xiv, 4, 26, 38, 39, 48, 138, 139, 141, tetracycline, 203 165, 166, 167, 239, 242, 248, 332, 341, 342, 346 tetracyclines, 201, 203 tonsillitis, vii, xiii, xiv, 4, 140, 141, 143, 152, 153, Texas, 187, 308 154, 162, 163, 164, 166, 167, 168, 173, 200, 203, Th cells, 338 331, 332, 333, 335, 336, 337, 339, 340, 341, 342, Thai, 77 343, 346, 358 thalamus, 11, 32 torus, 311 thallium, 316, 321 total iron binding capacity, 354 therapeutic approaches, 75 total parenteral nutrition, 185 therapeutic interventions, 46 total serum protein, 350 therapeutics, 41 toxic, 4, 146 therapists, 80 toxic gases, 146 thermal energy, 243 toxicity, 29, 218, 222, 227, 228 thoracic, 10, 58, 83, 225, 261 toxin, 8, 14, 23, 31, 40, 44, 70, 199, 200, 209 thorax, 255 trace elements, xiv, xv, 176, 347, 348, 349, 350, 352, threatening, 206, 250, 258, 259, 261 353, 354 three-dimensional, 85, 185 trachea, xi, 51, 56, 58, 66, 150, 249, 253, 264, 271 three-dimensional space, 185 tracheoesophageal fistula, 173 threshold, 37, 182 tracheostomy, 17, 30, 31, 58, 63, 64, 259, 301 throat, x, xi, 3, 4, 27, 67, 88, 193, 195, 196, 197, traction, 7, 19, 52, 57, 180 198, 200, 202, 203, 204, 205, 206, 207, 211, 212, trainees, 207, 208

Index 391 training, 27, 30, 69, 124, 176, 177, 178, 179, 185, two-dimensional, 84, 94 188, 275, 324 tympanic membrane, 89, 118 trajectory, 68 typhoid, 4 tranquilizers, 22 typhoid fever, 4 transcranial magnetic stimulation, 71, 73, 171 tyrosine, 43 transcription, 216 transcription factor, 216 U transducer, 122 transfer, 8, 280, 281, 284, 285, 287, 288, 289, 290, UES, 31, 51, 56, 58, 59, 60, 61, 63, 65, 68, 69, 172, 292, 294, 296 175, 178, 180, 181, 189, 267, 275, 301, 302, 305 transferrin, xiv, 347, 348, 349, 350, 352 ulcer, 4, 285, 291, 292, 293, 353 transformation, 223, 233 ulceration, x, 156, 184, 193, 195 transfusion, 256 ultrasonic vibrations, xi, 235 transient ischemic attack, 15 ultrasonography, 12, 13 translation, 81 ultrasound, 224, 239 translocation, 216, 223, 224, 226 ultrastructure, 298 translocations, 216, 223, 224, 232 uncertainty, 275 transmission, 3, 13, 26, 110, 146, 165, 199, 200, 205 uniform, viii, 1, 83, 145, 308 transplantation, 134, 135, 223, 226, 227, 233, 328 United States, 40, 70, 167, 190, 230 transport, 15, 28, 50, 53, 139, 171, 178, 187, 199, university students, 207, 208 315, 316, 343 unmasking, 333 transportation, 205, 349 upper airways, 144, 214 trapezius, 12 upper respiratory infection, 196, 211 trauma, viii, xi, xii, 6, 7, 10, 12, 13, 21, 24, 26, 49, upper respiratory tract, viii, 59, 79, 80, 88, 194, 199, 61, 63, 172, 173, 236, 237, 249, 250, 251, 252, 203, 250, 251 256, 257, 258, 259, 260, 261, 262, 263, 307, 358 urease, 201 traumatic brain injury, xii, 173, 299, 300, 301, 308 urethritis, 209 treatable, 19, 35, 157 urine, 176 tremor, 16, 21, 22, 24, 30, 43, 44, 60, 65, 70 usual dose, 221 trial, x, 21, 29, 34, 45, 67, 73, 106, 165, 169, 170, uveitis, 156 184, 208, 218, 227, 228, 231, 232, 247, 329 uvula, xv, 111, 113, 114, 118, 126, 145, 195, 197, trigeminal, 4, 23, 25, 27, 28, 51, 171, 174 198, 236, 237, 238, 240, 241, 342, 357, 358, 359, trigeminal nerve, 4 360, 361 trigeminal neuralgia, 25, 27 tuberculosis, 18, 141, 153, 163, 173 V tubular, 14 tularemia, 202, 211 vaccination, 3, 199 tumor, xii, 3, 5, 6, 7, 11, 14, 17, 18, 19, 42, 149, 173, vacuum, 237, 326, 330 174, 214, 215, 216, 217, 218, 219, 221, 222, 223, vagina, 4 224, 225, 227, 228, 233, 250, 256, 257, 279, 280, vagus, 2, 8, 23, 27, 40, 165, 214 282, 285, 286, 287, 290, 291, 292, 293, 294, 296, vagus nerve, 2, 8, 23, 27, 40, 214 297, 312, 313, 314, 315, 316, 317, 318, 332, 339 validity, 76, 191, 237 tumor cells, 11, 219, 312, 315, 316 values, 118, 119, 122, 266, 273, 274, 337, 338 tumor necrosis factor, 332, 339 vancomycin, 19, 201 tumours, viii, 49, 55, 214, 328 variability, 75, 111 turbinates, 243 variables, 205, 352, 353 turbulence, 115, 116, 236 variation, 97, 245 Turbulent, 236 vascular disease, 7, 12, 157 turgor, 176 vascular occlusion, 13 Turkey, 79, 193 vascular wall, 146 392 Index vascularization, 149 web, 333 vasculature, 324, 325 weight loss, 29, 37, 58, 174 vasculitis, 14, 157 wells, 202 vasoconstriction, 4 West Nile virus, 7, 11 vein, 6, 8, 12, 19, 26, 42, 251, 261 white blood cell count, 256 velo-cardio-facial syndrome, 131 white matter, 2 velocity, 11, 252 WHO, 5, 11, 16, 39, 41, 219 venography, 12 WHO classification, 219 ventilation, 16, 43, 237, 256 wine, 50 vertebrae, 249, 266, 295 winter, 194, 195, 196, 203 vertebral artery, 7, 41 women, 7, 13, 15, 147, 200, 242, 301 vesicle, 29 workers, 40, 146 vesicles, x, 8, 193, 198 workstation, 266 vessels, xi, 4, 9, 28, 146, 235, 239, 250, 255, 257, World Health Organization, (WHO) 4, 42, 204, 212 285, 287, 292 wound dehiscence, 280, 285 vibration, x, xi, 124, 235, 236, 244 wound healing, xii, xv, 57, 248, 279, 290, 291, 296, video clips, 186 298, 325, 326, 348, 353 videotape, 119, 301 writing, viii, 1, 33 viral hepatitis, 39 viral infection, 11, 39, 41, 194, 195, 205 X virulence, 156, 202 virus, x, 4, 7, 11, 26, 45, 193, 194, 195, 196, 198, X chromosome, 7 207, 208, 223, 224, 226, 230, 231, 233, 251, 257, xerostomia, 56, 64 262, 312, 319 X-linked, 7, 11, 41 viruses, x, 152, 193, 194, 197 x-rays, 62, 316 viscosity, 183 visible, 22, 157, 224, 273, 295, 335 Y vision, 3, 14 visual perception, 170 yawning, 26, 185 visualization, 117, 119, 120, 121, 128, 205, 244, yield, 205 275, 316, 333 yogurt, 183 vitamin A, 145, 150 young adults, 195, 196, 198, 201, 210, 219 Vitamin C, 28, 219 young women, 147 vitamins, 139 voice, 22, 23, 27, 29, 30, 34, 47, 61, 66, 70, 118, 119, 132, 144, 148, 162, 174, 179, 180, 185, 252 Z vomiting, 14, 197, 203, 204, 251 vulnerability, 96 Zenker's diverticulum, 77, 173 zinc, xiv, 61, 347, 348, 349, 350, 351, 352, 353, 355 Zinc, xv, 348, 353 W waking, 37, 144 walking, 170 warfarin, 16, 19, 251 warrants, 185, 186 watches, 124 water, 53, 72, 145, 171, 174, 176, 202, 243, 358, 359 weakness, 9, 11, 12, 13, 14, 20, 37, 54, 59, 61, 68, 114, 180, 182, 267, 268, 269, 270 wear, 86, 256