Head and Neck

EVALUATION OF NASAL OBSTRUCTION

2009-04-05T03:28:00.004-10:00

History and Physical Exam

History

Character of Nasal Obstruction: onset and duration, constant versus intermittent, unilateral (tumors, normal nasal cycle) versus bilateral obstruction, associated mouth breathing, snoring, anosmia/hyposmia/taste disturbances, tearing (nasolacrimal duct obstruction or allergy)
Contributing Factors: potential toxin and allergen exposure, known drug allergies, medications (see Table 1–1), history of immunodeficiency, asthma, sinusitis, otitis media, allergy, sleep disturbances, facial trauma or surgery
Associated Symptoms: allergic component (sneezing, itchy and watery eyes, clear rhinorrhea), sinus involvement

Antihypertensives
Psychotropic Medications
Oral Contraceptives
Chronic Nasal Decongestants: rhinitis medicamentosa
Cocaine: local vasoconstriction
Tobacco: irritates mucosa and impairs ciliary clearance
Antithyroid Medication
Aspirin: activates peripheral chemoreceptors
Marijuana

headaches), acute infection (fevers, malaise, purulent or odorous nasal discharge, pain)
Other Head and Neck (H&N) Symptoms: sore throat, postnasal drip, cough, ear complaints, halitosis, ocular pain, hoarseness
Think “KITTENS” for differential diagnosis (see Table 1–2)

Physical Exam

External Nasal Exam: external deformities (firmness, tenderness on palpation), nasal flaring, nasal airflow
Anterior Rhinoscopy/Nasal Endoscopy: examine twice (with and without topical decongestion), quality of turbinates (hypertrophic, pale, blue), quality of nasal mucosa, nasal septum, osteomeatal complex obstruction, foreign bodies, nasal masses, choanal opening
Quality of Nasal Secretions: purulent or thick (infectious), watery and clear (vasomotor rhinitis, allergy), salty and clear (CSF leak)
H&N Exam: facial tenderness, tonsil and adenoid hypertrophy, cobblestoned posterior pharynx, cervical adenopathy, otologic exam

Ancillary Tests

Allergy Evaluation: (see below)
Paranasal Plain Films: may be considered for screening, largely been replaced by CT/MRI
CT/MRI of Paranasal Sinus: indicated if obstruction may be secondary to nasal masses, polyps, or complicated sinusitis

Tabel 1-2 Differential diagnosis of Nasal Obstruction
(K) Congenital	Infectious & Idiopathic	Toxins & Trauma	Tumor (Neoplasia)	Endocrine	Neurologic	Systemic
Neurogenic tumors	Infectious rhinitis	Nasal and septal fractures	Papillomas	Diabetes	Vasomotor rhinitis	Granulomatous diseases
Congenital nasopharyngeal cysts	Rhinoscleroma	Medication side effects (rhinitis medicamentosa)	Nasal Polyps	Hypothyroidism		Vasculitis
Teratoma	Chronic sinusitis	Synechia	Hemangiomas	Pregnancy		Allergy
Choanal atresia	Adenoid hyperplasia	Environmental irritants	Pyogenic granulomas			Cystic fibrosis
Nasoseptal deformities		Septal hematomas Foreign bodies	Juvenile nasopharyngeal angiofibromas Malignancy

Biopsy: indicated for any mass suspect for malignancy, avoid biopsy of vascular neoplasms (juvenile nasopharyngeal angiofibroma, sarcomas) or encephaloceles
Rhinomanometry: provides an objective measurement of airway resistance, largely not utilized in clinical practice since highly time consuming, not cost effective, and inaccurate
Ciliary Biopsy and Mucociliary Clearance Tests: electronmicroscopy and ciliary motility studies for ciliary defects
Nasal Secretion Protein and Glucose: evaluate for CSF leak if suspected
Culture and Sensitivity: surgically obtained cultures usually indicated for complicated acute rhinosinusitis and resistant chronic sinusitis
Pulmonary Function Tests: suspect reactive airway disease component
Olfactometry: qualitative and quantitative testing of olfactory substances

Physiology of the Nasal Airway

2009-03-13T00:32:00.002-10:00

Nasal Cycles and Respiratory Airflow

nasal airflow is regulated through the volume of the venous sinusoids (capacitance vessels) in the nasal erectile tissue (located primarily in the inferior turbinate and to a lesser extent in the anterior septum)
the hypothalamus continuously stimulates a sympathetic tone (via the superior cervical sympathetic ganglia) to maintain a level of nasal vasoconstriction
inspired air is warmed to body temperature and is humidified to almost 100% humidity
Sneeze Reflex: induced by allergens, ammonia, viral infections, exercise, and other irritants which stimulates trigeminal afferents, complex efferent input results in a slow inspiratory phase, glottic and velopharyngeal closure (increases subglottic pressure), followed by a sudden glottic opening (sneeze)
Regulation Response Types

Asymmetrical Congestive Response (The Nasal Cycle): normal physiological congestion/decongestion cycle alternating between nasal sides every 2–7 hours
Symmetrical Congestive Response: temporary bilateral congestion induced by exercise, changes in body position, hyperventilation, cold air, sulfur, histamine, and other irritants; lasts 15–30 minutes

Microvasculature

regulates nasal volume, humidity, and heat exchange
Resistance Vessels: arterioles and precapillary sphincters, regulate blood flow to the nasal mucosa
Subepithelial Capillaries: fenestrated vessels allow for transport of solutes and fluids
Venous Sinusoids: capacitance vessel, determines blood volume and nasal congestion
Arteriovenous Anastomoses (AVA): regulate nasal blood flow by allowing blood to flow directly from the resistance vessels to the venous sinusoids

Regulation of Nasal Microvasculature

Sympathetic Innervation: provides vasoconstrictor tone to arteries and capacitance veins, mediated through Norepinephrine (primary neurotransmitter), Neuropeptide Y (a weak vasoconstrictor, enhances effects of norepinephrine), and Avian Pancreatic Polypeptide (APP)
Parasympathetic Innervation: controls secretions and dilates resistance vessels, mediated through Acetylcholine (primary neurotransmitter), Vasoactive Intestinal Peptide (VIP), and Peptide Histamine Isoleucine (PHI)

Nasal Valves

External Nasal Valve (Nasal Vestibule): anterior nostril (nasal alar cartilage, columella, and nasal sill), potential cause of obstruction during inspiration
Internal Nasal Valve (Limen Nasi): bordered by septum, anterior edge of the inferior turbinate, and caudal edge of upper lateral cartilage; narrowest segment (50% of total nasal resistance), potential site of obstruction secondary to Bernoulli’s principle (narrowed segment accelerates nasal airflow resulting in a decrease in intraluminal pressure)

Mucociliary System

Function: humidification, cleaning of inspired air, eliminating debris and excess secretion from paranasal sinus and nasal airway
Mucociliary Flow: mass motion of mucous layer in the paranasal sinus of the mucous blanket at 1 cm/min (eg, migration in the maxillary sinus begins at the floor of maxillary sinus natural ostium nasal cavity nasopharynx)
Components

Ciliated, Pseudostratified Columnar Epithelium: anterior border begins at limen nasi
Double Layered Mucous Blanket: deep, less viscous, serous periciliary fluid (sol phase) and superficial, more viscous, mucous fluid (gel phase)
Mucous Producing Glands: goblet cells (columnar cells, basal nucleus, secretory granules at lumen end), deep and superficial seromucinous glands (serous or mucous acini with cuboidal duct complexes), and intraepithelial glands (20–50 mucous cells around a single duct)

Major Composition of Nasal Mucus: 95% water, 3% glycoproteins (mucin), 2% salts, immunoglobulins (IgA), lysozymes (bacteriolytic), and lactoferrin (bacteriostatic)

Prosthetic Rehabilitation of Cancers Involving the Face

2009-02-21T23:20:00.000-10:00

Cancers that involve the facial structures such as the eye, ear, and nose, may require removal of a portion or all of the involved structures. In such cases, a removable prosthesis can be made to restore the appearance of these structures. After evaluation by a head and neck surgeon, the patient is referred to a dental oncologist for examination prior to surgery. Photographs and facial impressions may be made prior to surgery to document existing facial contours. An explanation of the procedures and the time required to make the prosthesis is discussed with each patient before surgery. Pictures of patients with similar diseases before and after surgery are available to view and discuss.

After an appropriate period allowing for healing, the patient is scheduled for initiation of the prosthesis fabrication process. This takes approximately five to seven visits, and in some cases, these appointments can last several hours. Special types of skin adhesives retain most prostheses. Implants similar to dental implants can be used to retain the prosthesis in some cases. These prostheses are made of silicone and require removal and cleaning every week. The average lifetime of a facial prosthesis is approximately two years.

Some prostheses can be remade in the laboratory and sent to the patient in the mail while others will require the patient to make an appointment with the dentist for evaluation before a new prosthesis can be made. In some instances surgically removed tissues can be reconstructed with compatible tissues from other parts of the body. In this case, a prosthesis may or may not be indicated or needed. When indicated, the reconstructed tissue may need surgical revision before a prosthesis is constructed. Treatments such as radiotherapy and chemotherapy can delay the fabrication of a facial prosthesis. These delays are necessary to allow proper healing of the tissues that will support and retain the prosthesis.

Radiation Therapy and Your Mouth

2009-02-21T23:18:00.000-10:00

Radiation therapy is a common type of treatment for cancer of the head and neck region. There are several important glands in this region called salivary glands. The major function of these important glands is the production of moisture (saliva) in the mouth. When the salivary glands are included in the treatment area, they may be damaged, limiting the amount of saliva produced. This is important because saliva is responsible for a number of important functions in the mouth. As far as teeth are concerned, saliva helps to prevent tooth decay. It also lubricates soft tissues such as the tongue, cheeks, and lips, which helps prevent irritation, which may occur during the normal process of speaking, eating, and swallowing.

Radiation therapy can also affect the jawbones by reducing the size of blood vessels supplying blood to them. Since blood vessels carry cells responsible for defense against bacteria, this can decrease the ability of the jaws to fight infection. Another very important side effect of radiation therapy is that it may cause scar tissue to form in the muscles and joints (temporomandibular joint-TMJ). If this occurs you may not be able to open your mouth to eat normal bites of food or adequately clean your mouth.

These side effects can be classified as short and long term problems. Short-term problems may include infection (bacterial, fungal, or viral), change in taste, pain, bleeding, and inflamed oral tissues commonly called mucositis. Mucositis is similar to a sunburn on your skin. In some patients this may become painful and interfere with eating. Long-term problems include permanent dryness (xerostomia), tooth decay (caries), decrease in the ability to open the mouth wide (fibrosis).

An infection in the jaws called osteoradionecrosis can result in a loss of a portion of bone and tissue covering the bone (ORN, osteoradionecrosis). How severe these problems become is related to the radiation dose, size of the treatment field, degree of mouth dryness, and the quality of the patient's oral hygiene. Prevention and treatment of the complications are discussed in separate areas of this web page (see Oral care Instruction Sheet and Physiotherapy Instruction Sheet).

Special Devices Used During Radiation Therapy

2009-02-21T23:13:00.002-10:00

Special treatment devices, known as radiation stents, may provide significant benefit to the patient and radiotherapist by assisting in the delivery of the radiation to precise local areas and thereby limiting complications following therapy. Not all patients undergoing head and neck radiation therapy will have a stent fabricated. The need for a radiation device is determined by the treating radiotherapist. If a stent is to be made, it can be used to protect (shield) or displace vital structures outside the treatment field, place diseased tissues within a daily repeatable position during treatment, position the beam, or maintain radioactive material at the tumor site.

At the first appointment, impressions are usually made of the upper and lower jaws and stone models are subsequently made from those impressions. A jaw registration composed of wax is made to approximate the upper and lower jaws in the treatment position. The stone models are placed into the wax registration and mounted onto an instrument so that the jaw relationship is reproduced. The radiation device is initially prepared in wax and verified in the patient's mouth prior to it being finalized. The completed radiation stent is usually made of an acrylic resin and may or may not contain a shielding lead alloy, depending upon several conditions: type of radiation given, condition of the diseased hard and soft tissues, oral opening ability, and the needs of the treating radiotherapist. Although use of these devices is usually confined to the head and neck region, they are occasionally of advantage in other accessible areas.

Supracricoid Partial Laryngectomies

2009-02-21T23:11:00.001-10:00

The Supracricoid Partial Laryngectomies (SCPL) are a subset of surgical procedures that are available to the Head and Neck Surgeon for the management of selected cancers of the larynx. The SCPLs are a subset of conservation laryngeal operations.

SCPL refers to the resection of the diseased or affected part of the larynx that is removed at the time of operation. The defect in the larynx is then reconstructed at the time of operation with what is known as a crico-hyoidal impaction. The specific type of impaction is either a cricohyoidoepiglottopexy, a cricohyoidopexy, or a tracheocricohyoidoepiglottopexy. Exactly which reconstruction is used is determined by the location of the patient’s cancer, the extent of involvement of the tumor and the patient's overall condition. The SCPLs are all alike in that the anterior component of the vocal cords is removed bilaterally in addition to the immediate area above and below the vocal cords. If the tumor then extends either above or below the actual vocal cords (or glottis), then either of the above reconstructions is performed. In addition, one of the arytenoids (the cartilage that controls the vocal cords) can also be removed.

The benefits of the SCPLs are that rather large tumors can be effectively removed from the larynx while still preserving swallowing, speech and the airway functions of the larynx. While the patient's voice will never be normal after any of the supracricoid partial laryngectomies, the patient is able to communicate readily without the aid of any prosthesis or electronic device, and most importantly, the vast majority of patients do not need a permanent tracheostomy. A tracheostomy is necessary in the immediate post-operative period, but we are usually able to remove this in the few days after surgery, before the patient even leaves the hospital. Then, as the surgery and tracheostomy sites heal, the patient relearns how to speak and swallow. Obviously then, if we can avoid the permanent hole in the neck needed with more traditional laryngeal surgeries, then the patient can lead a more normal and active life with fewer, if any, restrictions.

The SCPLs do, however, have some contraindications. Not everyone is a candidate for conservation laryngeal surgeries, and very specific criteria have to be met to be able to perform the resection and reconstruction while still removing the entire tumor. Obviously, the first goal of any cancer operation is to remove all of the cancer. In addition, pulmonary function must be assessed before performing any of the above surgeries. While patients recuperate from their surgery, there is often a moderate amount of aspiration of saliva and even diet into the airway. While the patient relearns to swallow in usually no more than seven to ten days, it is important that he have healthy lungs so that he can tolerate this small degree of aspiration. In addition, SCPLs do not give patients a normal voice. Patients are, however, able to communicate readily and without the use of any assisted devices.

Once a patient is found to have cancer of the larynx, it is then up to his treating surgeon to assess the extent of the disease and consider the patient's surgical options. If SCPL is an option, then we like to use it as we feel that not only is the patient’s long-term function significantly improved as compared to traditional therapy but also long-term cancer control is not sacrificed.

TNM Staging

2009-02-21T23:07:00.000-10:00

Traditionally, patients have had the impression that tumors are staged on a scale I (best prognosis) through IV (worst prognosis). While this has been true in the past, it has also been found that generic terms like stage I, II, III, or IV are not useful in planning treatment nor does it give enough information to all the members of the healthcare team who may participate in a patient's care. Therefore, in 1988, a committee called the American Joint Committee on Cancer was established to address this issue. This committee created a new method of staging for cancers throughout the body and fine tuned the staging methodology for the head and neck. TNM staging can still be converted to the traditional stage I-IV, but most physicians now talk of tumors in terms of their TNM staging.

The T in TNM stands for tumor. Tumors are graded on a scale of 0-4. T0 means that there is no evidence of the primary tumor at the time of diagnosis (an unusual but not uncommon occurrence). T4 usually refers to later, more invasive and larger tumors which involve adjacent structures, including the muscles, neck, etc. The "T-staging" varies for different parts of the head and neck. For example, tumors of the oral cavity (the region in the mouth from the lips to the tonsils) are staged as T1 if the tumors are 0 to 2 cm. in size, T2 if they are 2-4 cm. in size, T3 if they are greater than 4 cm. in size, and T4 if there is nerve involvement, involvement of bone, or extensive spread of tumor. However, this cannot be applied to all regions of the head and neck.

The N in TNM refers to node status. The "N-staging" is used for all types of head and neck cancers. The "N-staging" ranges from N0 (no evidence of nodal metastasis) to N3 (extensive nodal disease usually greater than 6 cm. in size). N1 refers to metastasis into lymph nodes which are on the same side as the primary tumor and which are smaller than 3 cm. N2 refers to tumors that are 3 to 6 cm. in size. The N2 classification is further broken down to A, B, and C. N2A refers to tumors on the same side as the primary tumor, measuring 3-6 cm. in size. N2B refers to tumors with nodes in several different areas of the neck but none greater than 6 cm. and all on the same side as the primary tumor. N2C refers to lymph nodes on the opposite side of the neck from the primary tumor or on both sides of the neck. N3, then, generally refers to massive nodal disease, which usually signifies a late stage or extensive nodal metastasis.

The M in TNM staging refers to metastasis or distant metastasis. M0 means that there is no evidence of distance metastasis at the time of initial presentation and M1 means that there is evidence of metastasis to any other site in the body outside of the head and neck.

The TNM staging, while sometimes quite difficult for the lay person to understand, is very useful to practicing head and neck oncologists in that it provides a common language for head and neck oncologists to communicate with when discussing cancer patients. It is still possible to break down the TNM staging into the traditional stage I-IV tumor staging system for patients; however, most patients will most likely hear their tumors described with TNM staging. The prognosis for each TNM stage varies based on the location of the primary. For each "T-stage", however, the presence or absence of nodal disease is highly significant in the prognosis. The worst prognostic sign in cancers of the head and neck (and most commonly squamous cell carcinoma) is the presence of nodal metastasis. While the presence of nodal metastasis is by no means a hopeless situation, lymph node metastasis does imply later disease, and more aggressive treatment is usually indicated.

Tracheoesophageal Puncture

2009-02-21T23:05:00.000-10:00

The tracheoesophageal puncture procedure for alaryngeal voice restoration is one method that a person who has had a total laryngectomy can use to talk following removal of the larynx. TE speech is often chosen because of its similarity to normal laryngeal speech. The method involves the creation of a tracheoesophageal puncture (TEP) at the time of the laryngectomy, or later when the patient is well healed. The opening is maintained by a prosthesis that acts as a one-way valve by allowing lung air to pass into the esophagus for sound production when the stoma is covered. At the same time, it prevents food and liquid from entering the trachea. When TEP is done after the laryngectomy, it usually involves a minor surgery that can be done on an outpatient basis.

The operation involves the creation of a small opening in the wall that separates the trachea (windpipe) and the esophagus. After the surgeon has performed the puncture, a small red rubber catheter is placed in the puncture to keep it from closing and to allow it to form adequately before the voice prosthesis is placed. The catheter is usually left in place 3-7 days before it is removed and the TE voice prosthesis is fit. Most patients do not complain of any discomfort while the catheter is in place and go about their daily routine without difficulty. During this short period of time, patients are usually able to eat and drink normally without problems.

There are many different kinds of prostheses. Selection depends upon the physical characteristics and comfort level of the patient. Most of the time, 3-5 visits are required to properly size, fit, and teach the TE speaker to manage and use the voice prosthesis. The TE speaker usually covers the stoma with a finger or a thumb to divert pulmonary air through the prosthesis into the esophagus for sound production. The actual sound is produced by the vibration of the walls of the esophagus. The sound is then shaped by the movement of the articulators, lips, tongue, teeth, etc. to form words and conversation just as the normal laryngeal speaker does. Some tracheoesophageal speakers are successful using a tracheostomal breathing valve instead of a finger to occlude the stoma. With this device, normal breathing is uninhibited, but the valve closes automatically during exhalation for speech production, enabling the patient to speak with both hands free.

Most patients are evaluated prior to TE puncture by a trained speech pathologist who assumes the responsibility for or participates with the physician in evaluating the potential of the esophagus for sound production to ensure TE speech success. Once the appropriate prosthesis has been fit, the TE speaker is taught to clean, remove, and reinsert the prosthesis. He or she is also shown how to apply and remove the tracheostoma valve should this device be used.

Care and maintenance of the prosthesis is not difficult. Most patients independently remove and replace it without problems. Other patients prefer to have their prosthesis replaced by their speech pathologist or physician. The average TE voice prosthesis lasts 2-3 months before it is removed, and a new one is reinserted. However, some patients are able to wear the prosthesis for much longer periods of time, up to and in some instances, beyond one year, before they need to remove it. Other patients find that they need to remove the prosthesis sooner. Again, the speech pathologist assists the TE speaker in selecting the appropriate prosthesis and developing a management routine to maximize the longevity of the voice prosthesis and to avoid problems.

The key to tracheoesophageal speech candidacy is good sound production. Usually the only contraindication to tracheoesophageal puncture is continued alcohol abuse and impaired cognitive-mental functioning. Pulmonary function must be adequate to support sound generation. Manual dexterity and good vision are important but not absolutely imperative for those patients who rely on the speech pathologist, physician or significant other to replace the prosthesis. The use of adaptive devices such as the tracheostoma breathing valve provide automatic diversion of airflow, thereby eliminating the need for digital occlusion for some patients.

There are several factors that are not considered contraindications to tracheoesophageal puncture procedures. These include diabetes, unilateral or bilateral neck dissections, and radiation therapy. The patient's medical status and surgical requirements should always be evaluated by the physician prior to tracheoesophageal puncture so as to ensure success postoperatively. Patients who have had extended surgical procedures including removal of other structures as well as the larynx may also be candidates. Good preoperative evaluation will determine appropriate candidacy.

The method of tracheoesophageal speech restoration offers many laryngectomees the potential for spontaneous, effortless speech production. It is important, however, that patients be evaluated properly and discuss their options with trained medical professionals prior to puncture to ensure postoperative TE speech success and avoid communicative frustration.

Videostroboscopy of the Larynx

2009-02-21T23:04:00.000-10:00

Videostroboscopy is a clinical evaluation tool, which allows one to directly observe the apparent motion of the larynx. This examination provides valuable information beyond that which the naked eye can see. It gives the clinician information regarding vocal fold vibration as well as an immediate and magnified image of the presence or absence of pathology. It can also document small changes in the vibratory capacity of the larynx as a result of a specific treatment modality. The presence of abnormal vibration may be detected using videostroboscopy long before the actual pathology becomes visually detectable to the naked eye. Videostroboscopy also provides a permanent record for documentation and comparison. Videostroboscopy has been found to be a valuable means for evaluating the degree of infiltration by cancerous lesions. Stroboscopy is also a very useful way to evaluate patients with vocal fold paralysis, because the onset of any improvement can often be observed earlier and with greater accuracy than with the eye or the ear.

Videostroboscopic evaluation of laryngeal functioning is routinely and easily performed in a clinic setting using either a rigid or flexible fiberoptic endoscope. In order to perform rigid oral endoscopy, the patient is asked to protrude the tongue and the clinician holds the tongue as a rigid tube is inserted into the mouth. The tube or scope, projects a high intensity light at a predetermined angle illuminating the structures to be observed and recorded. The advantages of this method are high illumination, a wide field of view, and excellent imaging capability. The disadvantages are that the procedure does interfere with normal speech production and there is some minor patient discomfort associated with the natural gag mechanism. However, the patient's discomfort is minimized with the use of a topical anesthetic spray.

Flexible fiberoptic endoscopy is performed with a flexible tube which is inserted through the nasal passage. Again, a high intensity light is transmitted through the flexible scope, which illuminates the structures to be viewed by the clinician, and/or recorded. In this procedure, one advantage is the excellent image of the vocal folds along with other structures of the oral cavity and throat. Since the small flexible scope is inserted through the nose, it does not interfere with the patient's ability to speak during the examination. The disadvantages are that the image is smaller than the image provided by rigid endoscopy, and the brightness of the image may be reduced. Again, possible patient discomfort is minimized with the use of a topical anesthetic spray administered into the nasal cavity. Both procedures allow the patient to go about their daily routine following completion of the evaluation.

The entire examination takes approximately 3-5 minutes, depending upon the experience of the examiner and the cooperation of the patient. Correct interpretation of the results requires knowledge and familiarity with the anatomy and physiology of the larynx, phonation, and the effect of potential pathologies on the vibratory functioning of the larynx. The technique is only one part of a clinical examination and is a valuable supplement to other currently used diagnostic procedures.

Xerostomia

2009-02-21T23:00:00.000-10:00

Dry mouth (Xerostomia) is caused by a lack of normal salivary function, through either a reduction in salivary flow or alteration of salivary composition. Three pairs of major salivary glands (parotid, submandibular, and sublingual) and an abundance of minor salivary glands scattered throughout the oral cavity produce saliva. The combined product of these glands provides a complex fluid, consisting of antibodies, electrolytes, proteins, glycoproteins, and lipids. Many studies have shown that saliva plays a significant role in the health of the teeth and oral mucosa.

Individuals who have had a decrease in the amount of saliva can exhibit many problems with their teeth and oral mucosa. Such manifestations can include increased dental caries, dehydration of the mucosa (mucositis), and oral infections, which will lead to discomfort and difficulty in chewing, swallowing, and speaking.

The most common causes of xerostomia include medical treatments and systemic disorders. The medical treatments that interfere with salivary function are medications, radiotherapy, surgery and trauma. Radiation therapy for head and neck cancer causes permanent salivary gland damage and is an important cause of xerostomia. The severity of xerostomia depends on the volume of tissue irradiated, length of therapy, radiation dose, and the amount of salivary gland tissue involved. Xerostomia may also be associated with a variety of systemic disorders, particularly Sjögrens syndrome (an autoimmune disorder that affects salivary and lacrimal functions as well as connective tissue), diabetes, scleroderma, and graft-versus-host disease as seen in bone marrow transplant patients. Many drugs, including analgesics, antidepressants, antihypertensives, and antihistamines can cause xerostomia.

Complications arising from dry mouth, such as increased dental caries, difficulty in swallowing, chewing and speaking, and an increased incidence of oral infection, can lead to nutritional deficiencies, and an overall decline in the quality of life. Additionally, patients with xerostomia have difficulty in wearing removable prostheses due to the dry mucosa and increased incidence of frictional denture sores.

The management of patients suffering from xerostomia can be a challenging dilemma for both dentist and patient. Xerostomia may be an early manifestation of a physiological disorder or an underlying salivary gland disease. Therapeutic options for relief of the symptoms of xerostomia is largely palliative, as reversal of the primary cause is often not possible. There can be a poor correlation between subjective reports and actual gland function as well as a large variation in degrees of salivary function found with xerostomia. Treatment is aimed initially at restoring the flow of saliva using mechanical means such as chewing sugar-free gum, taste stimulants, or systemic salivary gland stimulants (sialogogues). Artificial saliva substitutes and mouth wetting agents may be used, although the majority provide only short term relief of symptoms, and can cause irritation of oral tissues during long-term use.

METABOLICALLY ACTIVE TUMORS

2009-02-07T06:41:00.000-10:00

Tumors that arise from cells within the endocrine glands may secrete normal hormones in abnormal amounts. These cells derive from neural crest, neural ectoderm, or placodal ectodermal tissue that secrete monoamine (e.g., serotonin) or polypeptide (e.g., insulin) substances. These tumors are referred to as APUDomas (i.e., amine precursor uptake and decarboxylation) or neurocrinopathies. Tumor types include islet cell tumors, medullary carcinoma from the thyroid C cells, pheochromocytomas from adrenal chromaffin cells, and carcinoid tumors from Kulschitsky or enterochromaffin cells found in almost every organ of the body.

Carcinoid tumors are the most common of the APUDomas. They occur most frequently in the ileum and bronchus and have a high incidence of synchronous and metachronous neoplasms, whether carcinoid or other types of neoplasms. The active tumors secrete serotonin, although other substances (e.g., histamine, dopamine, substance P) have been suggested. The carcinoid syndrome includes flushing, diarrhea, cardiac valve disease, and occasionally wheezing. The mainstay of diagnosis is the 24-hour urinalysis for 5-HIAA, the major metabolite of serotonin. Treatment is surgical removal or pharmacotherapy to control the diarrhea and flushing using serotonin antagonists (e.g., cyproheptadine, methasergide), parachlorophenylalanine, or natural or synthetic somatostatin.

Pheochromocytomas are associated with “spells” and hypertension, either episodic (50%) or sustained (50%), which is difficult to differentiate from essential hypertension. The spells include a variety of symptoms, such as headache and acute anxiety or panic attacks with sweating. The rule of 10s applies: 10% are malignant, 10% occur bilaterally, and 10% are extraadrenal, occurring anywhere along the sympathetic chain from the skull base to the gonads. These types of tumors are usually called paragangliomas. Active tumors secrete norepinephrine alone (i.e., paragangliomas) or norepinephrine combined with epinephrine (i.e., adrenal tumors).

Tumors are diagnosed using 24-hour urinalysis for vanillylmandelic acid, computed tomography, 131I-metaiodobenzylguanadine, or ultrasound. All patients must be prepared for surgical excision with 7 to 14 days of a-adrenergic blockers. Phenoxyabenzamine is used orally beginning at a dose of 10 mg given four times each day and gradually increased to 300 mg daily until postural hypotension develops. A b-adrenergic blocker may be added 48 hours before surgery if the patient has tachycardia or arrhythmia or if the catecholamine profile shows excess epinephrine secretion. Propranolol is given in doses of 10 mg four times a day. Both medications are given the morning of surgery, and large amounts of intravenous fluid are used intraoperatively after tumor removal to counteract the marked increase in intravascular capacity, which can cause an acute fall in blood pressure. This occurs because the adrenergic stimulation is precipitously removed as the secreting tumor is removed.

Multiple Endocrine Neoplasia Syndromes

Several neoplastic syndromes involving multiple endocrine glands have been described. Currently, the favored nomenclature for the most well-established yndromes and their most commonly encountered neoplasias are listed. These syndromes are typically inherited in an autosomal dominant pattern; however, penetrance is variable.

MEN I is characterized by parathyroid, pancreatic, and pituitary neoplasias. The most common parathyroid neoplasia is multiglandular hyperplasia. Gastrin-producing islet cell tumors account for over half of the pancreatic tumors in MEN I and become the greatest source of morbidity in affected individuals. The most frequent pituitary neoplasm is a prolactinoma. Other endocrine tumors are unusual in patients with MEN I but may occur. The genetic mutation responsible for the syndrome occurs in the tumor suppressor gene, menin, and has been mapped to chromosome 11.

The distinguishing features of MEN IIa are medullary thyroid carcinoma (MTC), pheochromocytomas, and parathyroid tumors. MTC develops in hyperplastic C cells of the thyroid and is nearly universal in MEN IIa. Treatment consists of total thyroidectomy in all known cases and in unaffected carriers identified through prospective screening. Pheochromocytomas occur in over half of individuals and are typically bilateral and multicentric. They typically develop much later than MTC; however, when both are present, the pheochromocytoma should be removed first. Parathyroid hyperplasia is less frequent compared with MEN I, occurring in 10% to 35%. The genetic abnormality responsible for MEN IIa is a mutation of the RET proto-oncogene on chromosome 10. There is a 100% correlation between the presence of the RET mutation and MEN II and hereditary MTC. Thus, suspected carriers and family members are now being screened based on polymerase chain reaction techniques to identify carriers of the mutated RET proto-oncogene .

MEN IIb is characterized by MTC, pheochromocytomas, and mucosal neuromas. The mucosal neuromas are universal and predominantly involve the oral cavity and can involve other sites of the gastrointestinal tract and the conjunctiva, cornea, and eyelid. MTC in these patients is more aggressive than in MEN IIa, with metastatic disease developing in some children before age 1. The incidence of pheochromocytomas and their clinical course is similar to that of MEN IIa. Hyperplasia of the parathyroid glands is rare. The genetic mutation is also found in the RET proto-oncogene on chromosome 10; however, the specific point mutation is distinct from that causing MEN IIa.

Endocrine Emergencies

Hypercalcemic Crisis

Severe hypercalcemia, or hypercalcemic crisis, predominantly occurs in patients with advanced previously diagnosed malignancy. Serum calcium levels are typically elevated at least to 3.5 mmol/L (14 mg/dL); however, symptom severity also correlates with the rapidity of the calcium elevation. Ionized calcium levels are preferred for diagnosis and follow-up, as this is the physiologically active fraction. Clinical findings in emergent cases include hypovolemia, mental status changes, and gastrointestinal symptoms. Cardiac arrhythmias and renal dysfunction may also complicate the initial course.

Two separate mechanisms for malignancy-associated hypercalcemia are currently accepted. First, many solid tumors secrete a PTH-related protein (PTHrP) that has similar activity to PTH, although its production is unregulated. Squamous cell carcinoma of the lung, head and neck, cervix, esophagus, vulva, and skin, in addition to breast cancer, renal cell, and bladder cancer, are most commonly found to secrete PTHrP. Second, metastatic and hematogenous tumors produce local intercellular mediators that stimulate osteoclast activity. These cytokines (tumor necrosis factor beta, interleukin-6, etc.), once secreted by the tumor cells, act on the local osteoclast population to mediate bone resorption and calcium liberation.

Regardless of the underlying etiology, acute symptomatic hypercalcemia requires aggressive treatment. Initial efforts focus on rehydration. Volume contraction is universal and results from the osmotic diuresis and decreased glomerular filtration rate, which accompany uncontrolled hypercalcemia. Fluid replacement with isotonic saline should be started at 2 to 4 L/day. The use of loop diuretics to stimulate calciuresis is not performed routinely. Bisphosphonates (e.g., pamidronate) are osteoclast inhibitors and are considered first-line therapies for hypercalcemic crisis. Volume expansion and bisphosphonate therapy can normalize most patients’ serum levels. However, the rate of response with the bisphosphonates is 3 to 6 days for calcium normalization. In the critically ill patient, a more rapid response is desired. Calcitonin reduces calcium levels within hours by direct osteoclast inhibition, and its ability enhances renal calcium excretion. Its main drawback is its short-lived effectiveness. Gallium nitrate and plicamycin are no longer considered first-line therapy because the bisphosphonates have significantly better toxicity profiles. Glucocorticoids and dialysis are indicated in specific circumstances.

Hypocalcemia

Acute or emergent hypocalcemia is uncommon. The typical presentation centers around the neuromuscular irritability that predominates the clinical picture. Numbness, paresthesias, cramps, tetany, and seizures are often seen. Laryngeal tetany and cardiac arrhythmias can result in mortality if not treated immediately. When complicated or emergent hypocalcemia is suspected, intravenous elemental calcium should be administered until clinical improvement is observed. Preferably, 100 to 300 mg of calcium gluconate is given over 10 minutes. Ionized calcium levels should be obtained and followed until normalization occurs. Ideally, the underlying etiology will be identified and treated. The most common etiology in the practice of otolaryngology is hypocalcemia from sudden PTH deficiency, seen after parathyroid or thyroid surgery. Intravascular ionized calcium levels typically reach their lowest 24 to 48 hours after surgery. Additional causes of hypocalcemia include rapid intravascular protein binding, vitamin D deficiency, and PTH resistance. Several anions may also complex with ionized calcium to decrease the concentration precipitously, such as citrate, bicarbonate, and phosphate. One other scenario is the hungry bone syndrome most commonly seen after removal of larger adenomas in elderly patients.

Once the acute situation has been temporized, long-term calcium supplementation is instituted and may be enhanced with vitamin D, depending on the underlying etiology and the initial response to oral calcium therapy. Difficult cases may benefit from evaluation of serum phosphate and magnesium levels, because abnormal levels will complicate the diagnosis and treatment of hypocalcemia.

Thyroid Storm

Thyrotoxic crisis is an uncommon complication of thyrotoxicosis. It has become a rare complication in the surgical patient, and most commonly occurs in medical patients with known Grave’s disease and a precipitating event that leads to an acceleration or decompensation of their hyperthyroid state. Clinically, patients present in a severe hypermetabolic state. Fever, tachycardia, and sweating are nearly universal. Arrhythmias are common, and heart failure and shock may ensue. Motor restlessness and mental status changes are common. If unrecognized or untreated, stupor, coma, and hypotension develop, and the course ends in fatality.

Common precipitating events include other acute illnesses, infections, trauma, and emergent surgeries. Others include radioiodine therapy, parturition, toxemia of pregnancy, and diabetic ketoacidosis. Not all cases have identifiable precipitating events; however, they must be sought to properly treat the patient and avoid additional morbidity.

Diagnosis is based on the history and clinical presentation. Once the diagnosis is anticipated, treatment should begin before confirmation with laboratory testing. A scoring system has been devised for grading patients on the severity of their crisis.

There are three goals of therapy. First, treatment must focus on controlling the hyperthyroid state. Propylthiouracil is used first to prevent further synthesis of thyroid hormone and to limit the peripheral conversion of T4 to the more physiologically active T3. Iodide is used to block the release of preformed hormone stores from the thyroid gland. Lithium may be used in cases where iodide is contraindicated. Glucocorticoids are used routinely and are associated with improved survival. Definitive treatment of the hyperthyroidism occurs after reaching an euthyroid state with either radioactive 131I ablation or surgical excision. The second object of therapy is reestablishing a normal homeostatic state. Many of the acute manifestations can be controlled with b-adrenergic blocking agents. Propranolol has been used most extensively, but B1-selective agents have theoretic advantages in certain patients (e.g., heart failure, asthma, etc.). Other measures include volume reexpansion, electrolyte normalization, glucose monitoring, and treating the hyperthermia. Salicylates should be avoided because they increase the basic metabolic rate and displace bound thyroid hormone, thereby increasing serum levels. Cardiac arrhythmias may require pharmacotherapy and anticoagulation. The final goal of therapy is identifying and treating the precipitating trigger. Mortality from thyroid storm is still significant (15% to 20%), despite earlier diagnosis and aggressive treatment.

Myxedema Coma

Myxedema coma is the end result of chronic untreated hypothyroidism. It is typically seen in elderly women during the winter months. Most cases are initiated by a precipitating event such as an infection (35%), medications (e.g., sedatives), cold exposure, or an exacerbation of another chronic illness. Patients develop symptoms insidiously, and diagnosis may be delayed. Major clinical findings include hypothermia, altered mental status, and respiratory suppression. Typical skin changes include periorbital edema, peripheral edema, dry skin, and signs of anemia. Bradycardia is common. Progressive depression of the sensorium may result in coma. Early diagnosis is essential to limit morbidity and mortality. Once the diagnosis is suspected, treatment should begin. Confirmation with laboratory testing will reveal depressed T4 levels and elevated TSH.

Initial treatment may require respiratory assistance with mechanical ventilation. In addition, underlying illnesses need attention (pneumonia, heart failure, urinary tract infection, etc.). Thyroid replacement begins with an intravenous T4 bolus, followed by daily maintenance doses. Glucocorticoids are given routinely to prevent the potential complication of adrenal crisis. Passive measures are used to rewarm the patient, thereby avoiding rapid vasodilation and possible vascular collapse, which may accompany aggressive warming measures. Typically, a hyponatremia similar to SIADH is present and should be treated with free water restriction. Volume expansion should be accomplished with isotonic crystalloids or whole blood. Response to therapy occurs within the initial 24 hours and is evident by improvement of hypothermia, bradycardia, and mental status. Prolonged respiratory assistance is not uncommon. Mortality rates have improved to approximately 15% to 20% with aggressive treatment.

Diabetic Emergencies

Many of the complications of diabetes are true medical emergencies, including diabetic ketoacidosis, nonketotic hyperglycemic–hyperosmolar coma, and hypoglycemia. Additional characterization and therapeutic protocols for these conditions is beyond the scope of this chapter, and the reader is directed to the chapter on perioperative management issues.

PANCREAS

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Physiology

Pancreatic islet cells produce insulin, glucagon, human pancreatic polypeptide, and somatostatin. Insulin, derived from proinsulin, consists of an alpha and beta chain connected by a C peptide. The basal secretion level is raised in a biphasic response to stimulation. The rapid phase may release stored preformed insulin in response to glucose, amino acids, glucagon, and some gastrointestinal hormones. With continuous glucose administration, both preformed and new insulin is released in the delayed phase. Release is stimulated by the vagal nerve and b-adrenergic receptors and inhibited by b-adrenergic blockers, sympathomimetic amines (e.g., epinephrine, norepinephrine), and somatostatin, which also inhibits glucagon. Stress triggers the release of glucagon, glucocorticoids, GH, and catecholamines, which are antagonists to insulin, resulting in glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, and nitrogen wasting. Stress also affects wound healing, electrolyte and fluid balance, and susceptibility to infection.

Dysfunction

There are two types of diabetes mellitus with seemingly different causes, but they are both associated with similar complications. Type I (i.e., juvenile onset) usually appears in patients younger than 25 years who are insulin deficient, ketosis prone, and usually not obese. The cause is thought to be an autoimmune response to beta cells triggered by infection. The insulin levels of these patients are generally difficult to control. Type II (i.e., adult onset) has a more gradual onset. Patients are generally obese, over 40 years old, ketosis resistant, and more stable and easier to control. It is thought to be the more inheritable form of diabetes. Obesity reduces the number of insulin receptors on insulin-responsive cells, altering glucose tolerance. With fasting and weight loss, the number of receptors increases to normal levels.

In addition to random fasting blood sugar levels, screening for diabetes is accomplished with the 2-hour postprandial glucose tolerance test, using a fixed amount of glucose after a 3-day period of carbohydrate loading. Serum glucose determinations are 10% to 15% higher than whole blood determinations; therefore, it is important to know which test is performed.

Surgical diabetic patients under stress or anesthesia are thought to undergo hormone imbalances, causing glucose intolerance. They are also at greater perioperative risk due to disease-impaired cardiovascular, renal, and neurologic systems. Before surgery, careful assessment of these systems is important, as is assessing glucose control and modifying the patient’s regimen if necessary.

Symptoms of angina, which must be sought, may be absent. Autonomic dysfunction presents with orthostatic hypotension, nocturnal diarrhea, early satiety, or difficulties with erections and ejaculations in the male patient. Nocturia, dry mouth, blurred vision, weakness, palpitations, hunger, and nightmares are symptoms related to poor glucose control. The effects associated with hypoglycemia may be masked by neuropathies or b-adrenergic blockers (e.g., propranolol).

A thorough examination of the heart and peripheral pulses is necessary with an examination for bruits and orthostasis. An electrocardiogram should be obtained preoperatively and postoperatively to detect a silent myocardial infarction. Laboratory data should include preoperative fasting glucose, electrolytes, blood urea nitrogen, creatinine, chest radiograph, and clean-catch urinalysis. Long-term control can be assessed with the hemoglobin A1C determination, which is elevated with high glucose levels due to incorporation of glucose into the hemoglobin molecule. Levels remain elevated for 4 to 6 weeks, the lifespan of an erythrocyte. Before surgery, the patient in ketoacidosis should be stabilized as much as possible or surgery should be delayed to establish better glucose control or clear up bacteria in the urine. Diabetics are at increased risks for diseases with a predilection for immunocompromised patients, such as invasive fungal and bacterial infections. In addition, they suffer from poor wound healing, as may be evident after surgical procedures.

ADRENAL GLAND

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Anatomy and Physiology

The adrenal gland consists of the cortex and the medulla. The adrenal medulla is made of chromaffin cells that secrete norepinephrine and epinephrine in response to fear, anger, or stress. These hormones result in increased heart rate, raised blood pressure, vasoconstriction, and altered carbohydrate metabolism. The adrenal cortex is further divided into three zones that secrete five groups of steroids: corticosteroids, aldosterone, androgens, estrogens, and progesterone. All are derived from cholesterol. The outer region, the zona glomerulosa, secretes the main mineralocorticoid, aldosterone. Most of the glucocorticoids, androgens, and progesterone are secreted by cells in the middle, the zona fasciculata. The inner zona reticularis is responsible for the remainder of the steroids secreted by the cortex. This area atrophies in older males and enlarges with pregnancy and in the summer in women of childbearing age. Unlike the medulla, removal of the cortex is incompatible with life. The glucocorticoids are bound to transcortin, carrying 70% of the circulating cortisol.

Aldosterone secretion, the serum potassium level, and ACTH are controlled mainly by angiotensin II. It acts on the collecting duct of the kidney, the salivary glands, and the gut mucosa, causing the excretion of hydrogen and potassium ions in exchange for sodium ions.

Dysfunction

Hyperadrenocorticism

Hyperadrenocorticism causes Cushing’s syndrome, characterized by centripetal obesity with moon facies and buffalo hump, hirsutism, easy bruisability, amenorrhea, manic behavior or psychosis, osteopenia, muscle weakness, and violaceous striae of the abdomen, hips, and breasts. Excess of glucocorticoids leads to increased volume and blood pressure, hypokalemia, negative nitrogen balance, and glucose intolerance because they are insulin antagonists. The causes include pharmacologic administration of glucocorticoids or ACTH and pathologic conditions, such as an ACTH-producing pituitary adenoma, adrenal hyperplasia, adrenal adenomas or carcinomas, or secondary ectopic ACTH production in some lung, thymus, or pancreatic tumors. Presentation of ectopic ACTH production may be atypical, including hyperpigmentation due to the stronger melanocyte-stimulating hormonelike properties. Cushing’s syndrome usually presents in the third to sixth decade of life and occurs more commonly in women. At surgical exploration, 75% to 90% of these cases are due to corticotropic cell adenomas with autonomous secretion and are therefore not under hypothalamic control. In the other 10% to 25%, no pituitary tumor is found.

Adrenocortical Insufficiency

Primary adrenocortical insufficiency (i.e., Addison’s disease) may be due to destruction of the gland from autoimmune disease, tumors, infection, hemorrhage, or metabolic failure in hormone production. Secondary causes are hypopituitarism or suppression by exogenous steroids, ACTH (e.g., autonomous tumors), or endogenous steroids. The disease is characterized by fatigability, weakness, anorexia, nausea and vomiting, weight loss, hyperpigmentation, hypotension, and occasionally hypoglycemia. In women, the loss of adrenal androgens causes a loss of axillary and pubic hair. The absence of glucocorticoid causes volume depletion with decreased cardiac output and function, leading to shock that is sometimes called addisonian crisis.

Overproduction of Aldosterone

Primary overproduction of aldosterone is due to an adenoma (i.e., Conn’s syndrome) or nodular hyperplasia of the zona glomerulosa and is associated with moderate hypertension, hypokalemia, alkalosis, and normal or slightly increased sodium levels. Symptoms include muscle weakness, nocturnal polyuria, and cramping of the hands. Secondary excess is seen in cirrhosis, ascites, the nephrotic syndrome, and with diuretic use if the patient is volume depleted. In primary overproduction, tests show elevated aldosterone levels with severely suppressed plasma renin levels that do not respond to volume depletion; in secondary overproduction, one finds renin levels that are not suppressed and that may rise using various methods. Congenital or infantile forms of hypoaldosteronism are due to an enzyme defect in production. In the elderly, the condition is thought to be caused by an intrinsic renal problem, causing inadequate renin production. Many patients are diabetic and present with moderate renal insufficiency and serum potassium levels that are much higher than expected.

THYROID GLAND

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A detailed discussion regarding the thyroid gland and its associated diseases can be found in Chapter 114. The following discussion focuses on the endocrinology of the thyroid gland.

Physiology

Thyroid hormone affects the metabolic rate and plays a critical role in thermogenesis from increased energy release and higher oxygen consumption required by the stimulation of various processes. These processes include actions involved in fetal and neonatal growth, especially of the brain; glucose, amino acid, and electrolyte transport into the cell; oxidative phosphorylation; and protein, carbohydrate, and lipid metabolism. Thyroid hormone increases production of lipogenic enzymes and induces production and storage of fat in times of excess carbohydrate ingestion.

The thyroid gland converts iodine into thyroid hormone by organification. Oxidized iodine attaches to the 3 and 5 positions of tyrosine in the thyroglobulin molecules, which then couple by oxidation, forming tetraiodothyronine or T4 10 times more abundantly than T3. The hormone–thyroglobulin complex is stored as the colloid at the center of the cluster of thyroid follicle cells. To release thyroid hormone, thyroid follicular cells form pseudopodia, creating vesicles by endocytosis. These contain lysosomes that hydrolyze the thyroglobulin using hydrogen supplied by reduced glutathione, freeing thyroid hormone for release into the circulation by exocytosis. Organification is blocked by propylthiouracil and reducing substances used to treat hyperthyroidism. Release is inhibited by iodine, which affects production of glutathione reductase.

TSH from the pituitary stimulates the synthesis and release of thyroid hormone from the thyroid gland, which then exerts feedback inhibition directly on the pituitary thyrotropic cell by competing with thyrotropin-releasing hormone from the hypothalamus. After release into the circulation, thyroid hormone is bound to thyroid-binding proteins, mostly T4-binding globulin (70% to 80%), albumin, and transthyretin, to keep the hormone soluble in plasma and assist with distribution to the cells. A minute amount circulates freely in the plasma. It is this part that diffuses into the cell and is carried to the nucleus by binding proteins. Here it stimulates DNA transcription, resulting in the formation of messenger RNA and the production of various proteins. T4 binds with 10 times higher affinity to the thyroid-binding globulin, and T3 binds preferentially to intracellular sites. Therefore, most T4 is found in the circulation, and most T3 is found within the cells. The amount of free hormone can be affected by drugs that displace bound hormone (e.g., aspirin in high doses, phenytoin, carbamazepine) and severe nonthyroidal illness, which reduces the ability to bind thyroid hormone. Binding proteins are elevated by acute hepatitis, elevated estrogen (e.g., pregnancy, birth control pills, postmenopausal estrogen), or methadone and are reduced by anabolic steroids, nephrotic syndrome, or decreased production due to an inherited disorder.

Most T4 is secreted by the thyroid gland. It is functionally a prohormone but may have some metabolic activity itself. Conversion to T3, the more metabolically active form, occurs by monodeiodination in the liver, kidney, and possibly other organs, which accounts for 80% of the circulating T3. During stress or nonthyroid illness, T4 preferentially converts to inactive reverse T3 to conserve the body’s metabolism by removal of an iodide from the inner ring, instead of the outer ring as in T3. The deiodinase system is inhibited by fasting, systemic illness, kidney or liver disease, acute psychiatric illness, severe vomiting of pregnancy, and drugs (e.g., propylthiouracil, glucocorticoids, propranolol, iodine-containing agents), leading to the accumulation of reverse T3 and a fall in T3 levels. Large amounts of T4 are stored in the thyroid gland and bound in the circulation to thyroid-binding globulin, thereby prolonging the time for hormone deficiencies to manifest themselves clinically. Inflammation may cause injury to the gland with leakage of thyroglobulin, causing elevated levels of T4, T3, thyroglobulin, and other iodinated products in the serum.

PARATHYROID GLANDS

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Parathyroid anatomy and physiology and its pathologic states are discussed thoroughly in Chapter 115. The following discussion highlights the role of PTH in the regulation of calcium metabolism.

Calcium Metabolism

Calcium homeostasis depends on the release of PTH and on small amounts of vitamin D and calcitonin. The function of the parathyroid glands is to maintain calcium and phosphorus homeostasis. Calcium is important for the formation of intercellular ground substance, teeth, and bone. At the membrane level, it affects neuromuscular irritability, muscular contractility, and cardiac rhythmicity. Lack of extracellular calcium causes tetany and death if not corrected.

PTH is a peptide of 84 amino acids with an active amino-terminal end and an inactive carboxy-terminal end. Its secretion by the parathyroid glands is enhanced by a low ionized serum calcium and a high phosphate level.

Calcitonin, a peptide of 32 amino acids, is produced by the parafollicular C cells of the thyroid and contributes to calcium homeostasis by suppressing osteoclastic activity in bone and decreasing the amount of calcium available to the extracellular space. Calcium circulates in the extracellular compartment in three forms: 47% is ionized and is the free and active form that is readily used; 47% is bound to albumin and globulin and fluctuates with the serum protein level; and 6% is bound to anions such as bicarbonate, phosphate, and citrate.

Calcium is pumped from the extracellular compartment into the intracellular space. When serum calcium falls, the parathyroids release PTH, which increases osteoclastic activity, causing resorption of bone and release of calcium; increases resorption of calcium at the renal tubular cell; increases absorption of calcium from the gastrointestinal tract; stimulates renal-1-hydroxylase, which allows 1-hydroxylation of vitamin D in the kidney; and increases excretion of phosphorus in the urine, decreasing the serum phosphorus level.

Vitamin D is produced from exposure to sunlight or is obtained from the diet. Dietary calcium is provided by dairy products, green vegetables, nuts, fish, and calcium supplements. Approximately 1 g of calcium is ingested each day, and most of this is absorbed in the duodenum and upper jejunum. 1,25-Dihydroxyvitamin D increases the uptake of calcium at the brush border of the intestine by increasing cellular ATP and alkaline phosphatase content. At the other end of the cell, calcium is extruded into the extracellular fluid in exchange for sodium. The inactive vitamin D is transported by carrier protein to the liver, where it is 25-hydroxylated. It is then transported to the kidney, where 1-hydroxylation takes place, and it becomes activated to perform its function in maintaining calcium homeostasis by increasing calcium absorption and increasing calcium release from bone by osteoclastic activity.

SURGICAL ANATOMY OF THE HEAD AND NECK

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Anatomy is the basic science of all surgery. Surgery in the region of the head and neck cannot be considered safe unless the surgeon thoroughly understands the anatomy of this area and its important variations. Although anatomic structures and the relations between them do not change, our knowledge of anatomy must be continually updated to meet the challenge of new surgical techniques and approaches. This chapter is overview of surgical anatomy of the head and neck with a focus on the major regions. It is not a substitute for thorough anatomic knowledge, which can be gained only through intensive study in a cadaver laboratory and an operating room.
THE CRANIUM
Scalp
The cranium is covered by the hair-bearing scalp, which is divided into layers of skin and subcutaneous tissue, galea aponeurotica, loose connective tissue, and periosteum or pericranium covering the calvarial vault. The blood supply of the scalp comes from the paired supraorbital and supratrochlear arteries anteriorly, the terminal branches of the superficial temporal arteries laterally, and the occipital vessels posteriorly. This rich vascularity provides a network on which small scalp flaps can be based and rotated, as in the management of male pattern baldness. Sensation to the scalp is provided by branches of cranial and spinal nerves.
Calvaria
The bony vault of the cranium, the calvaria, consists of the unpaired frontal bone, the paired parietal bones, and the unpaired occipital bone (Fig. 1.1). In the lateral aspect, the greater wing of the sphenoid bone and the temporal bone complete the cranium. There is a rich layer of diploic bone between the inner and outer tables of the calvaria. This is a source for split-thickness calvarial bone grafts, which often are used in head and neck reconstruction. The calvarium is thickest at the external occipital protuberance and in the parietal region. It is thinnest over the temporal region. This allows ready access for neurotologic operations on the middle fossa. The venous circulation of the calvaria is provided by diploic veins, which drain to the veins of the scalp or into the dural venous sinuses. In some instances the diploic veins are connected to each other, and this communication allows osteomyelitis that originates in the frontal sinus to involve the frontal bone, scalp, and dura.
Cranial Fossae
The intracranial cavity is roughly divided into three fossae. The anterior or frontal cranial fossa contains the paired frontal lobes and provides access to the nasal cavity for the olfactory nerves through the cribriform plate. The crista galli provides superior midline extension of the nasal septum. The middle cranial fossa contains the temporal lobes. In this important junction of the cranial cavity, the middle meningeal artery arises from the foramen spinosum, and the trigeminal nerve enters through the superior orbital fissure (V1), the foramen rotundum (V2), and the foramen ovale (V3). Cranial nerves II, III, IV, and VI, which traverse the cavernous sinus and enter the orbit, also course through the middle cranial fossa. The internal carotid artery is in its place in the carotid siphon as it traverses the cavernous sinus in this region. The posterior cranial fossa contains the paired cerebellar hemispheres and the brainstem. In this location, the internal auditory meatus is associated with the seventh and eighth cranial nerve complex. The jugular foramen, transverse sinus, and foramen magnum are the major landmarks of the posterior cranial fossa.
EYELID, ORBIT, AND EYE
Eyelids
The upper and lower eyelids are similar in structure, although the upper eyelid is more mobile and has features not found in the lower eyelid. The space between the eyelids is known as the palpebral fissure, which is limited medially and laterally by the canthi. At the medial canthus is the lacrimal caruncle, where there is a small lake of tears and the tiny papillae of the lacrimal duct system. The conjunctiva is a thin mucous membrane layer that covers the inner aspects of the eyelids and extends onto the surface of the globe.
Tarsus
The upper tarsal plate provides rigidity to the upper eyelid and is larger than the lower tarsus (Fig. 1.2). Each eyelid consists from without inward of skin, subcutaneous tissue, voluntary muscle of the orbicularis oculi, orbital septum, tarsus, smooth muscle, and conjunctiva. The more freely mobile upper lid receives the insertion of the levator palpebrae superioris muscle. The orbicularis oculi is the sphincteric muscle of the upper and lower eyelids. It attaches at a medial palpebral ligament and spreads in an arc laterally and inferiorly to provide a sphincteric muscle to the eye. It receives innervation from the temporal and zygomatic branches of the facial nerve. This muscle interdigitates with the frontalis muscle and the corrugator supercilia.
Blood Supply
The arterial supply of the eyelids is provided by the angular branch of the facial artery, which forms an anastomotic network with the supraorbital and supratrochlear artery and shares a small contribution from the superficial temporal vessels. The veins of the eyelids are larger and more numerous than are the arteries and drain into the ophthalmic and angular veins medially and the superficial temporal vein laterally. Accompanying the peripheral arterial arcade of the upper eyelid, the veins of the small venous plexus drain into the ophthalmic vein, which drains posteriorly to the cavernous sinus. The veins in this region of the face do not have valves and may propagate septic emboli posteriorly. This is a particularly dangerous situation for patients who have infections in the areas of the eyelids or periorbital abscess. These patients are at risk of cavernous sinus thrombosis.
Lacrimal System
The lacrimal apparatus consists of a secretory portion, the lacrimal gland, its ducts, the drainage apparatus, the lacrimal canaliculi and sac, and the nasolacrimal duct (Fig. 1.3). The lacrimal gland is partially divided into two portions by the lateral horn of the aponeurosis of the levator palpebrae. The larger orbital portion of the gland lies in a shallow fossa on the frontal bone and is in contact anteriorly with the orbital septum. The excretory ductules of the lacrimal gland run through the orbital part of the gland, run through or close to the posterior part of the palpebral portion, and are joined by ducts from this portion. Removal of the palpebral portion can destroy the drainage of the entire gland.
Movement of the eyelid distributes tears over the surface of the eye, and any excess tends to accumulate in the lacrimal lake. This structure drains into the paired superior and inferior canaliculi and from there into the lacrimal sac. The lacrimal sac is housed in the bony lacrimal fossa of the medial orbital wall. This drains into the nasal lacrimal duct and eventually into the inferior meatus of the nose.
Orbit
The bony orbit consists of the medial wall occupied largely by the ethmoid bone, lacrimal bone, and a portion of the nasal process of the maxilla (Fig. 1.4). The floor of the orbit consists of the roof of the maxilla. The inferior orbital fissure is at its lateral extent. The zygomatic bone and greater wing of the sphenoid form the lateral orbital wall and join the frontal bone superiorly to complete the pyramidal bony orbit. On its medial aspect are the paired ethmoidal foramina, which provide a route to the orbit for the anterior and posterior ethmoidal arteries. The optic canal posteriorly transmits the optic nerve and ophthalmic artery. The superior orbital fissure transmits cranial nerves III, IV, V, and VI and provides an aperture for the ophthalmic vein.
Eye
The eye consists of the cornea and sclera in the anterior aspect. The anterior chamber protrudes as a second sphere on the structure of the orbit. The lens and iris form the posterior portion of the anterior chamber. Contained within the substance of the eye is the vitreous. The retina rests on the choroid. The fovea centralis is the focal point of the eye. Asymmetric to the structure of the orbit is the insertion of the optic nerve and ciliary arteries.
The seven voluntary muscles of the orbit are the levator palpebrae superioris; the superior, inferior, medial, and lateral rectus muscles; and the superior and inferior oblique muscles (Fig. 1.5). The smooth muscles of the orbit are the orbitalis muscle, the superior and inferior tarsal muscles, and ciliary and iridial muscles within the eye. The superior oblique is supplied by cranial nerve IV, the lateral rectus by cranial nerve VI, and the other voluntary muscles of the orbit by cranial nerve III. The tarsal and orbital muscles (of Müller) are supplied by sympathetic fibers derived from the carotid plexus and from the superior cervical ganglion. The dilator pupillae, the sphincter pupillae, and the ciliary muscle are supplied by parasympathetic fibers through the oculomotor nerve (III).

The primary blood supply to the orbit is through the ophthalmic artery. The primary drainage is through the ophthalmic vein, which drains directly into the cavernous sinus. An additional anastomotic network is present on the anterior aspect of the face in the form of an arcade of vessels around the eyelids and through the pterygoid plexus.
THE EAR
The development and the anatomic and physiologic features of the ear are discussed in Chapter 128 and Chapter 129.
NOSE AND PARANASAL SINUSES
External Nose
The external part of the nose is a roughly pyramidal shape. The skeleton of the external nose is partly bony and partly cartilaginous and membranous. The nasal bones, which are usually narrow and thicker above, wider and thinner below, articulate firmly above with the nasal part of the frontal bone and with each other laterally with the nasal process of the maxilla (Fig. 1.6). Attached to the inferior aspect of the nasal bones are the upper lateral cartilages. These are continuous with the cartilaginous septum. In the inferior aspect, the lobule of the nose is formed mostly by the lower lateral cartilages, which consist of a medial and lateral crus. There are several small cartilages within the nasal ala. The chief arterial supply of the nose is from the facial artery through the angular artery and superior labial arteries. Venous drainage is similar, with a component gaining access to the ophthalmic vein through draining vessels from the trochlear and angular veins.
Nasal Cavity
The nasal cavities are also known as the nasal fossae. The nasal septum consists of the nasal septal cartilage, the nasal crest of the maxilla, the nasal crest of the palatine bone, the vomer, and the perpendicular plate of the ethmoid bone. The lateral nasal wall is formed by the prominent nasal turbinates. The meatus are situated below the corresponding turbinates (Fig. 1.7). The inferior meatus provides drainage for the nasolacrimal duct. The middle meatus provides drainage for the anterior nasal sinuses, namely the frontal sinus, anterior ethmoid sinuses, and the maxillary sinus. The superior meatus provides drainage for the posterior sinuses, namely the posterior ethmoid and sphenoid sinuses.
The arterial supply of this region is from internal carotid sources through the anterior and posterior ethmoid arteries and from an external carotid source through the sphenopalatine artery. Contributions also may exist from the greater palatine vessels and the septal branch of the superior labial artery. These form an important anastomotic network in the anterior septum known as the Kiesselbach plexus, which accounts for most nosebleeds.
Sinuses
The paranasal sinuses consist of the paired frontal, ethmoid, maxillary, and sphenoid sinuses (Fig. 1.8). The frontal sinus develops as one of several outgrowths from the region of the frontal recess. Two, three, or even more frontal sinuses on a side have been reported, and some persons have no frontal sinus. The degree of pneumatization of the frontal sinuses varies. Pneumatization may extend into the roof of the orbit and laterally into the frontal bone as far as the sphenoid wing. The frontal sinuses drain into the anterior aspect of the middle meatus.

Ethmoid Sinuses
The ethmoid sinuses consist of a variable number of separate cavities that honeycomb the ethmoid bone between the upper part of the lateral nasal wall and the medial wall of the orbit. The anterior ethmoid cells are divided into frontal recess cells, which open into the frontal recess of the middle meatus; infundibular cells, which open into the ethmoid infundibulum; and bullar or middle ethmoid cells, which open directly into the middle meatus on or above the ethmoid bulla. There may be one to seven posterior ethmoid cells. The bullae and posterior ethmoid cells may encroach on each other and overlap, the bullar cells spreading backward or the posterior cells forward. The posterior ethmoid cells drain into the superior meatus.
Sphenoid Sinus
The sphenoid sinus usually opens into the sphenoethmoidal recess above and behind the superior nasal concha. The ostium usually is in the posterior wall of the recess, but sometimes it is on its lateral wall. The degree of pneumatization of the sphenoid sinus varies. This variation is an important factor in surgical approaches to the pituitary gland. The relations of the sphenoid sinus are important because of the surrounding anatomic structures. The optic nerves are superior to the sinus, and the internal carotid artery is lateral to the sinus within the cavernous sinus. The maxillary nerve lies in the inferior lateral portion of the sinus in the anterior aspect. The hypophysis lies within the posterior superior portion of the sphenoid sinus and can be approached through transsphenoidal hypophysectomy.
Maxillary Sinus
The maxillary sinus usually is the largest of the paranasal sinuses and is situated in the body of the maxilla. Its anterior wall is the facial surface of this bone, and its posterior wall is the infratemporal surface. Its medial wall is that of the nasal cavity. The roof of the maxillary sinus is also the floor of the orbit, and it also may be affected in blowout fractures of the orbit. The maxillary sinus drains into the middle meatus of the nasal cavity. The roots of the posterior molar teeth may extend into the sinus. The maxillary sinus is bounded posteriorly by the pterygomaxillary fossa, through which course the terminal branches of the internal maxillary artery. These vessels can be approached through the maxillary sinus for relief of epistaxis.
THE FACE
Facial Bones and Muscles
The bones of the face include the frontal and nasal bones and the facial bones proper—maxilla, mandible, zygomatic, and palatine bones. The facial and mimetic muscles are divided into five chief groups concerned with the mouth, nose, orbit, ear, and scalp (Fig. 1.9). The platysma muscle in the neck also belongs to the facial group. The chief action of these muscles is on skin into which they insert. All these muscles are innervated by the facial nerve.
Parotid Gland
The parotid gland, which is anterior to and below the lower part of the ear, extends subcutaneously backward over the anterior portion of the sternocleidomastoid muscle, forward over the masseter muscle, and deeply behind the ramus of the mandible to lie between the mandible and the external acoustic meatus and mastoid process (Fig. 1.10). The gland is roughly divided into a lateral and medial portion by the course of the facial nerve. Related to the parotid gland are several periparotid and intraparotid lymph nodes, which may swell. The parotid gland drains through the parotid duct. It is innervated by the auriculotemporal nerve from the otic ganglion.
Facial Nerve
The anatomic characteristics of the facial nerve vary in the extracranial portion of the nerve. Identification of the nerve depends on marking the position of the posterior belly of the digastric muscle, the external meatal cartilage, the tympanomastoid suture line, and the styloid process.
ORAL STRUCTURES
Maxilla
The maxilla is the chief component of the upper jaw (Fig. 1.11). In addition to housing the dental apparatus and the maxillary sinus, it is related posteriorly to the medial and lateral pterygoid plates. The hard palate unites the paired maxilla and forms the bony roof of the oral cavity. Sensation to the upper teeth is provided by the maxillary nerve through the posterior superior and anterior superior alveolar nerves. The infraorbital nerve, another branch of V2, provides sensation over the face of the maxilla and soft tissues.
Palate
The palate intervenes between the nasal and oral cavities (Fig. 1.12). It consists of the maxilla, the horizontal process of the palatine bone, and the pterygoid plates. Soft tissues covering this area form the hard and soft palates of the roof of the mouth. The skeletal core of the soft palate is the palatine aponeurosis. The most superficial muscle fibers on the pharyngeal surface of the soft palate are those of the palatopharyngeus muscle. The levator veli palatini, tensor veli palatini, and uvular muscle complete the structures of the soft palate.

Mandible
The mandible, or lower jaw, consists of the tooth-bearing body and the ramus that extends upward from the angle of the mandible. The ramus, including the angle, is covered externally by the masseter muscle, which is crossed by the facial nerve and parotid duct. Between the ramus and the medial pterygoid muscle are the inferior alveolar and lingual nerves. Overlapping the posterior border of the ramus is the parotid gland, and within and paralleling this border is the upper portion of the external carotid artery. The superficial branch of this artery emerges from the parotid gland behind the temporomandibular joint, and its internal maxillary branch runs transversely deep to the ramus. Inferiorly and medially, the angle and posterior part of the body of the mandible are related to the submandibular gland, and medially, the anterior part of the mandible is adjacent to the sublingual glands. The musculature most intimately concerned with the mandible and its movements consists of the masseter, temporal, and two pterygoid muscles (Fig. 1.9). These muscles govern mastication and are innervated by the third division of the trigeminal nerve.
Hyoid Bone and Tongue
The hyoid bone, to which are attached infrahyoid and suprahyoid muscles, effectively separates the anterior suprahyoid and infrahyoid fascial compartments. The suprahyoid muscles are the digastric and stylohyoid muscles, the mylohyoid and the geniohyoid muscles, and the muscles of the tongue (Fig. 1.13). The extrinsic muscles of the tongue are the genioglossus, the hyoglossus, and the styloglossus. The intrinsic muscles of the tongue are complicated bundles of interlacing fibers, among which are connective tissue septa. The midline septum lies between and effectively separates the muscles, nerves, and vessels of the two sides. It is an almost bloodless midline plane.
Submandibular Gland
The submandibular gland occupies most of the submandibular triangle and expands beyond this area over the superficial structures of the anterior and posterior bellies of the digastric muscle (Fig. 1.14). Its posterior border is close to the lower part of the parotid gland at the angle of the jaw, where it is separated from this gland by the stylomandibular ligament. The submandibular gland is crossed superficially by the facial vein and sometimes by the ramus mandibularis branch of the facial nerve. The larger submandibular lymph nodes lie along the superficial upper border of the gland, between it and the mandible. The anterior portion of the submandibular gland lies directly against the mylohyoid muscle and the mylohyoid nerve. Medial to the mandible and above the level of the submandibular gland is the lingual nerve in its course toward the tongue. When the submandibular gland is removed, the facial vein is sacrificed, but the ramus mandibularis branch of the facial nerve is preserved to avoid disruption of the corner of the mouth. The facial artery passes across the upper surface of the gland, usually grooving it deeply before rounding the lower border of the mandible, and must be sacrificed in removal of the gland. The submandibular and sublingual glands are innervated from the submaxillary ganglion fibers that accompany the sensory fibers of the lingual nerve. These fibers originate in the chorda tympani and pass into the submandibular ganglion.
PHARYNX AND LARYNX
The wall of the pharynx consists of mucosa and voluntary muscle. The mucosal structure of the pharynx varies. That of the nasal part is ciliated and resembles the mucosa of the nose. In the rest of the pharynx, the epithelium is stratified squamous tissue. The muscular wall of the pharynx with its thin covering of buccal pharyngeal or visceral fascia is separated from the prevertebral fascia by an area of loose connective tissue that constitutes the retropharyngeal space.
Nasopharynx
The nasal part of the pharynx, the nasopharynx, is continuous anteriorly through the choana with the nasal cavities (Fig. 1.15). The floor is the upper surface of the soft palate. The fornix or roof, the mucosa of which is attached close to the base of the skull, slopes downward and backward to become continuous with the posterior wall. The eustachian tubes are prominent on the lateral aspect of the nasal pharynx. There may be adenoid tissue in the superior recess of the nasopharynx.
Oropharynx
The oropharynx is continuous anteriorly through the fauces, or oral pharyngeal isthmus, with the oral cavity. The boundaries of the fauces are the posterior border of the soft palate above, the palatine arches laterally, and the dorsum of the tongue. Below the fauces, the anterior wall of the pharynx is the posterior or pharyngeal dorsum of the tongue. On the posterior parts of the dorsum of the tongue lie irregular nodules of tissue known as the lingual tonsils. The lateral wall of the passageway of the fauces houses the large palatine tonsils. The lingual tonsils in the anterior aspect, the palatine tonsils in the lateral aspect, and the pharyngeal tonsils or adenoids in the posterior and superior aspects form a ring of lymphoid tissue known as the Waldeyer ring.
Hypopharynx
The laryngeal part of the pharynx, or hypopharynx, extends from just above the level of the hyoid bone superiorly to the lower border of the cricoid cartilage inferiorly, narrowing rapidly to become continuous with the esophagus. The anterior wall is formed laterally by mucosa on the medial surface of the thyroid cartilage and centrally or medially by the larynx and its appendages. Above is the epiglottis and the aditus of the larynx. Below the aditus, the anterior wall of the pharynx is also the posterior wall of the larynx. Lateral to the epiglottis are the lateral glossoepiglottic folds that form the anterolateral boundary between the oral and laryngeal parts of the pharynx. Below these folds, the hypopharynx extends forward around the sides of the larynx between this area and the thyroid cartilage. These bilateral expansions are the piriform recesses or sinuses.
The intrinsic portion of the larynx consists of the epiglottis, false vocal folds, laryngeal ventricles, paired true vocal folds, and arytenoid cartilages in the posterior aspect. Contained within the aryepiglottic folds are the paired corniculate and cuneiform cartilages. The space between the two vocal folds is the glottis.
The muscles of the pharynx are the superior, middle, and inferior constrictors. These muscles look like ice cream cones inserted into one another. They gradually merge to form the cricopharyngeus muscle at its inferior extent and then the esophagus. Each constrictor inserts with the corresponding muscle of the opposite side and the midline into a posterior midline raphe. These muscles are innervated by cranial nerve X through the pharyngeal plexus. Dehiscence in the pharyngeal constrictors may give rise to Zenker diverticula. Immediately lateral to the pharyngeal muscles are the great vessels of the neck and cranial nerve X.
Larynx
The major structural elements of the larynx are the shield-shaped thyroid cartilage and cricoid cartilages (Fig. 1.16). They join through the cricothyroid joint. The superior cornua of the thyroid ala articulate through several small cartilages with the hyoid bone. Overlying the structure of this skeletal framework are the infrahyoid muscles, which include the paired sternohyoid, sternothyroid, omohyoid, and thyrohyoid muscles.
The epiglottis is formed of fibroelastic cartilage and has multiple perforations that allow free access of lymphatic drainage or tumor to the preepiglottic space. The preepiglottic space is a C-shaped space bounded superiorly by the median glossoepiglottic ligament, inferiorly by the thyroid cartilage, anteriorly by the thyrohyoid membrane, and posterolaterally by the epiglottis and aryepiglottic folds. Free dissemination of tumor can occur within the preepiglottic space. The paired arytenoid cartilages provide an attachment for the vocal ligament and movement of the vocal folds. The intrinsic muscles of the larynx are innervated by the recurrent laryngeal nerve. The exception is the cricothyroid muscle, which is innervated by the superior laryngeal nerve. The recurrent laryngeal nerve enters inferiorly and laterally to the cricothyroid articulation through the Killian-Jamieson area. The recurrent laryngeal nerve on the left originates over the aortic arch and ascends in the neck to innervate the larynx. On the right, this structure goes around the subclavian artery.
THE NECK
Cervical Triangles
The prominent landmarks of the neck are the hyoid bone, the thyroid cartilage, the trachea, and the sternocleidomastoid muscles (Fig. 1.17). The sternocleidomastoid muscles divide each side of the neck into two major triangles, anterior and posterior. The anterior triangle of the neck may be further delimited by the strap muscles into the superior and inferior carotid triangles. The posterior triangles or lateral triangles of the neck are formed by the posterior border of the sternocleidomastoid muscle anteriorly, the clavicle inferiorly, and the anterior border of the trapezius muscle posteriorly. The omohyoid muscle divides this triangle of the neck into a small inferior subclavian triangle and a larger posterior occipital triangle. Deep to these muscles are the scalenes, which form much of the muscle mass of the posterior and lateral portions of the neck. The brachial plexus and subclavian artery course between the anterior and middle scalene muscles. The subclavian vein courses anteriorly to the anterior scalene muscle.
Inferior Portion of the Neck
In the inferior root of the neck and closely associated with the brachial plexus are the paired phrenic nerves that course medially to innervate the diaphragm (Fig. 1.18). These nerves originate in the ventral rami of the cervical plexus of the third, fourth, and fifth cervical nerve rootlets. The subclavian artery gives rise to the thyrocervical trunk. The transverse cervical and suprascapular arteries typically course laterally over the surface of the phrenic nerve. This relation allows identification of these structures. The vagus nerve lies further medially and is contained within the carotid sheath. It shares the sheath with the common, internal, and external carotid arteries and jugular vein. Posterior to the carotid sheath lies the cervical sympathetic nerve. On the surface of the carotid sheath lie the ansa hypoglossi nerves.
Lateral Portion of the Neck
The dominant structure of the lateral cervical triangle is the spinal accessory nerve. It emanates from the posterior border of the sternocleidomastoid muscle in close association with the splay of nerves of the cervical sensory plexus. It innervates the trapezius muscle on its inferior aspect in close association with the transverse cervical artery or suprascapular artery, which variably supplies the trapezius muscle.
Arterial Supply
The two common carotid arteries differ in length because the right carotid usually arises from the brachycephalic artery behind the sternoclavicular joint, and the left arises from the arch of the aorta (Fig. 1.19). Both arteries end by bifurcating into the internal and external carotid arteries. Over the lateral aspect of these arteries course the paired hypoglossal nerves. The internal carotid artery is situated more posteriorly and has no branches. The external carotid artery has branches and lies slightly anteriorly. This information can be crucial in differentiating the two vessels for ligation. From its origin, the internal carotid artery ascends directly toward the carotid canal and is crossed laterally, in ascending order, by the hypoglossal nerve, occipital artery, posterior belly of the digastric and associated stylohyoid muscle, and the posterior auricular artery. Still higher and close to the base of the skull, the external carotid artery is anterolateral to the internal carotid artery, and the stylopharyngeus muscle and associated glossopharyngeal nerve, the pharyngeal branch of the vagus, and the stylohyoid ligament all pass laterally to the internal carotid, between it and the external carotid artery.
After its origin in the carotid triangle, the external carotid artery passes upward, deep to the posterior belly of the digastric and stylohyoid muscles, crosses the styloglossus and the stylopharyngeus muscles on their lateral aspects, and parallel to the ramus of the mandible passes into the deeper portion of the parotid gland. The external carotid artery has branches to the superior thyroid, lingual, facial, ascending pharyngeal, occipital, posterior auricular, maxillary, transverse facial, and superficial temporal arteries.
Venous Supply
The veins of the neck vary considerably in their connections with each other and in their relative sizes (Fig. 1.20). Those conducting blood downward from the head and face include the external jugular, anterior jugular, internal jugular, and vertebral veins. At the base of the neck are the suprascapular and transverse cervical veins and the subclavian vein, which unites with the internal jugular vein to form the brachycephalic or innominate vein. The subcutaneous veins and the external and anterior jugular veins are especially variable in size and course.
Lymphatic Vessels
The lymphatic system of the neck consists of numerous lymph nodes intimately connected with each other by lymphatic channels and the terminations of the thoracic and right lymphatic ducts. The deep cervical lymph nodes are numerous and prominent, and many of them are large. They form a chain embedded in the connective tissue of the carotid sheath. Most are in that portion of the sheath around the internal jugular vein. They extend from the base of the skull to the base of the neck. Two nodes that deserve particular attention are the superior jugulodigastric node at the junction of the internal jugular vein and the posterior belly of the digastric and the inferior juguloomohyoid node at the junction of that muscle and the internal jugular vein. Block resection of the neck in a standard radical or modified manner relies on reproducible and consistent lymphatic drainage pathways for success.
Viscera
The visceral structures of the neck include the thyroid and parathyroid glands, a portion of the pharynx, the larynx, the trachea, the esophagus, and sometimes portions of the thymus (Fig. 1.21). The thyroid gland lies below and on the side of the thyroid cartilage covered anteriorly by the infrahyoid muscles. A pyramidal lobe of the thyroid may extend superiorly from the isthmus that connects the two lobes of the thyroid gland. On the posterior surface of the thyroid gland lie the paired parathyroid glands. Successful parathyroid exploration and thyroidectomy depend on accurate identification and preservation of the recurrent laryngeal nerves and identification of the parathyroid glands. Landmarks that are used successfully to locate these structures include the trachea, common carotid artery, and inferior thyroid artery, which form a triangle within which the surgeon usually finds the recurrent laryngeal nerve. Lymphatic drainage occurs along the peritracheal nodes. Venous drainage similarly is directed inferiorly along the inferior thyroid veins.
The four or more parathyroid glands develop from the dorsal extremities of the third and fourth pharyngeal pouches. As the thyroid and thymus and their associated parathyroid glands move caudally from the region in which they originate, the thymus normally descends beyond the level at which the thyroid halts. The parathyroids from the fourth pouches (superior parathyroid glands) typically are situated more craniad than the thyroid gland, and those derived from the third pouches (inferior parathyroid glands) are typically freed from the thymus and become associated with the thyroid gland at its lower pole. Both sets of parathyroid glands usually are situated on the posterior aspect of the lateral lobes of the thyroid gland, but there are many exceptions. Because of the manner in which they arise and migrate into the neck, the glands often are displaced and may be situated in other portions of the thyroid gland or lie above or below it.

PITUITARY

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Embryology and Anatomy

The pituitary gland lies within the sella turcica in the sphenoid bone. The sphenoid sinus wall forms the anterior and inferior aspect of the bony sella, giving direct access to the gland by this route. Soft-tissue boundaries include the lamina dura, forming the floor of the sella; the cavernous sinus with its contents laterally; the optic chiasm superiorly; and the diaphragma sellae, forming the dural roof. The blood supply of the pituitary is from the internal carotid system through the hypophyseal arteries. The predominant venous drainage is directly into the cavernous sinus system.

The gland is made of two embryologically and histologically distinct lobes. The posterior pituitary (i.e., neurohypophysis) is derived as an outpouching of the floor of the third ventricle and consists of nerve endings of neurons whose cell bodies reside in the supraoptic and paraventricular nuclei of hypothalamus. The neurohypophysis produces two octapeptides, oxytocin and vasopressin or antidiuretic hormone (ADH), which are mediated by neural reflexes. These control functions such as uterine contraction, milk letdown, and blood osmolality. The anterior pituitary (i.e., adenohypophysis) is derived from the oropharyngeal ectoderm of Rathke’s pouch and has no direct nerve supply. It is controlled by chemical messages released into the anterior pituitary blood supply from hypothalamic and posterior pituitary cells (hypophyseal–portal system) and is regulated by input from many parts of the brain and by feedback from target organs such as the thyroid, adrenal cortex, and gonads. It is made of distinct cell types that produce characteristic hormones. Originally, these were classed in three groups: acidophils, basophils, and chromophobes.

Physiology

Antidiuretic Hormone

ADH, also called arginine vasopressin, is the major posterior pituitary hormone in humans. Secretion is triggered by central nervous system osmoreceptors and baroreceptors supplied by cranial nerves IX and X. They respond to an increase of as little as 2% in plasma osmolality above 280 mOsm/kg or a decrease in circulating volume of about 10% precipitated by conditions such as hypotension, hypovolemia, and vomiting.

The two primary regions of the nephron affected by ADH are the medullary thick ascending Limb of Henle and the collecting duct. The ascending limb is the diluting segment, where most of the filtered load of sodium chloride is reabsorbed, developing medullary hypertonicity. ADH increases the water permeability of the collecting ducts, allowing osmotic equilibration of tubular fluid with the medullary interstitium, resulting in decreased urine volume.

Adrenocorticotropic Hormone

Adrenocorticotropic hormone (ACTH), a corticotropin, is derived from the prohormone proopiomelanocortin, which also contains melanotropins, lipotropins, and beta endorphin. Pulsatile secretion from the anterior pituitary follows a circadian rhythm and is responsive to certain stimuli (e.g., pain, hemorrhage, anxiety, pyrogens, hypoglycemia). The lowest level of ACTH in the serum occurs between 10 p.m. and 3 a.m. and peaks between 6 and 8 a.m. ACTH actions include stimulation of steroidogenesis by the adrenocortical cells, lipolysis in fat cells, amino acid and glucose uptake in muscle, the secretion of insulin by the pancreatic beta cells, and GH secretion by the somatotropic cells of the pituitary. Regulation of ACTH secretion is under hypothalamic control by corticotropin-releasing factor and feedback inhibition by circulating adrenal cortisol.

Thyroid-stimulating Hormone

Thyroid-stimulating hormone (TSH), a glycoprotein hormone, is produced by the thyrotropic cells of the anterior pituitary gland. TSH increases concentrations of cyclic AMP in the thyroid gland, resulting in the phosphorylation of key proteins and leading to increased size and vascularity of the gland, increased follicular epithelium height, reduction of the amount of colloid, increase in iodide transport, stimulation of the synthesis, and release of thyroxine (T4) and triiodothyronine (T3).

Regulation is somewhat complex. Secretion is stimulated by hypophyseal thyrotropin-releasing hormone and inhibited by hypophyseal somatostatin and anterior pituitary growth hormone. Negative feedback of secretion is by T3, the major inhibiting hormone. Intracellular T3 regulates TSH secretion, but plasma T4 levels correlate better with TSH release. When serum T4 approaches the lower limits of normal, TSH begins to rise exponentially. Of the intracellular T3, 75% is derived from conversion of plasma T4 by 58-deiodinase and the remainder comes from plasma T3 uptake.

Growth Hormone

Growth hormone (GH) is secreted by somatotropic cells. Secretion is pulsatile and peaks 2 to 3 hours into sleep (i.e., stage III or IV). The major actions involve the stimulation of bone and cartilage growth, nitrogen and protein metabolism, fat metabolism, carbohydrate metabolism, and soft-tissue growth (3). Secretion is regulated by hypothalamic peptides. It is stimulated by GH releasing hormone (GH-RH), or somatocrinin, and inhibited by somatostatin. Somatomedins and GH inhibit release by promoting somatostatin release. Exercise, stress, some neurogenic stimuli, and central a-adrenergic agonists augment secretion, but emotional deprivation in some children, a-adrenergic blockers, and b-adrenergic agonists inhibit secretion.

Prolactin

Prolactin is a single-chain peptide similar to GH. It is secreted in a diurnal pattern by the lactotropic cells of the anterior pituitary gland. Peak secretion occurs in the later hours of sleep. Prolactin acts directly on the mammary gland to initiate and maintain lactation but requires preparation of the breast tissue by estrogens and progesterone. It also acts on receptors on the granulosa cells of the ovary to inhibit follicular steroidogenesis.

Follicle-stimulating and Luteinizing Hormones

The glycoproteins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are secreted by the gonadotropic cells in the anterior pituitary gland. Secretion levels vary in premenopausal and postmenopausal women with a 3- to 15-fold increase in women after menopause. In men, FSH acts on the Sertoli’s cells to indirectly stimulate spermatogenesis, and LH acts on the Leydig’s cells to stimulate testosterone synthesis. In women, LH acts on multiple ovarian cells. The preovulatory surge is important in follicular rupture and luteinization. It alone stimulates progesterone and androgen production and is necessary for the normal secretion of estrogen. FSH acts on the granulosa cells to stimulate gametogenesis and also stimulates the production of estradiol. Ovulation is provoked by a combination of an elevated estradiol level and a midcycle rise in FSH level.

Regulation of secretion is by pulsatile release of gonadotropin releasing hormone (GnRH) from the hypothalamus, stimulating release of LH and FSH. Secretion is affected by gonadal steroids by means of a negative feedback mechanism, probably acting at the pituitary and the hypothalamus.

Dysfunction

Central hypothalamic diabetes insipidus is caused by inadequate synthesis or release of ADH. In 50% of cases, the cause is idiopathic. Other causes include basilar skull fractures, tumors of the intrasellar or suprasellar regions, encephalomalacia secondary to cerebrovascular accidents, and the histiocytoses associated with large temporal or mastoid lytic lesions. Patients who have undergone hypophysectomy are also at risk, but this complication is unusual now because of better surgical techniques and less pituitary stalk damage. Symptoms include polyuria (3 to 15 L/day), thirst, nocturia, hyposthenuria (specific gravity, 1.005), low urine osmolality (less than 200 mOsm/kg of H2O), and plasma hypertonicity (plasma osmolality more than 287 mOsm/kg H2O). Treatment is with Pitressin or 1-deamino-8-D-arginine vasopressin), which has negligible pressor effects and can be taken as a nasal spray.

The syndrome of inappropriate secretion of ADH (SIADH) is a common problem with numerous causes, including central nervous system infections, pulmonary diseases, trauma, many drugs, and bronchogenic or gastrointestinal cancers, especially oat cell tumors. The increased secretion of ADH causes retention of ingested water and hyponatremia.

Excess secretion of ACTH presents as Cushing’s syndrome. ACTH deficiency is associated with symptoms similar to those of Addison’s disease, except for the hyperpigmentation. Sodium and potassium levels are usually normal because aldosterone secretion is only partly regulated by ACTH; however, low cortisol levels may cause water retention with subsequent hyponatremia. With age, there may be diminished sensitivity of ACTH to negative feedback by glucocorticoids, and the ectopic ACTH syndrome is more common due to the increased incidence of malignancies.

The mean level of TSH is normally 1.8 mU/mL. This level may rise above 5 mU/mL when the plasma T3 and T4 are still within normal range in early hypothyroidism. Hypothalamic or pituitary failure prevents TSH levels from rising. TSH levels may be normal or slightly elevated in secondary hypothyroidism because TSH is not bioactive.

Excess GH secretion early in life is manifested as gigantism and as acromegaly after growth centers have closed. Deficiencies may be isolated or occur with other hormone deficiencies with or without an adenoma. If onset is early, the result is short stature; however, if it occurs with other deficiencies, the diagnosis may be difficult before puberty, because ACTH and TSH have large secretory reserves. With age, the plasma somatomedin C level is decreased, basal GH levels fall in females, the sleep-related pulsatile secretion declines, and the response to GH-RH or insulin-induced hypoglycemia may be attenuated.

Excess prolactin production is the most common hypothalamic–pituitary disorder in clinical endocrinology. The high levels inhibit the release of GnRH from the hypothalamus, causing hypogonadism. Failure of lactation is associated with deficiency of prolactin due to postpartum necrosis of the pituitary (Sheehan’s syndrome from ischemia caused by hemorrhage or shock), or it can be an isolated deficiency after an uncomplicated delivery. Pituitary necrosis also is seen in severe anoxia or long-standing diabetes mellitus.

Pituitary dysfunction can be related to developmental abnormalities associated with midline structural defects involving isolated or combined cell types. For example, Kallmann’s syndrome, due to the maldevelopment of the olfactory lobes and related hypothalamic lesions, is characterized by hyposmia or anosmia and an isolated GnRH deficiency with the associated gonadal dysfunctions. Pituitary necrosis is also seen in severe anoxia or long-standing diabetes mellitus.

Infectious causes include encephalitis, abscess, tuberculosis, or syphilis involving the hypothalamus or pituitary. A viral infection of selected neurohypophyseal nuclei may be a possible mechanism of acquired “idiopathic” diabetes insipidus. Other causes include noninfectious granulomas or infiltrations, such as the histiocytoses in children and sarcoidosis or excessive iron deposition from hemochromatosis in adults. In several autoimmune disorders, there may be circulating antibodies to lactotropic or somatotropic cells. Lymphocytic hypophysitis is seen in some postpartum women.

Pituitary damage can occur in children as a result of chemotherapy and radiation therapy. Accidental and surgical trauma is thought to be due to stalk separation or damage. In other cases, although the gross appearance is normal, abnormal hormones that are not biologically active may be produced.

Pituitary adenomas are classified by hormonal immunostaining of secretory granules within the cell or cells of origin and by radiologic appearance. Using computed tomographic or magnetic resonance studies, the tumor is classified as “enclosed” if there is no evidence of invasion of the bony sellar floor. Class I tumors or microadenomas are smaller than 10 mm in diameter, class II tumors or macroadenomas are larger than 10 mm in diameter, and invasive tumors are considered class III if part of the sellar floor is involved or class IV if all of the floor is destroyed. This classification does not limit the superior extension of the tumors. Functioning adenomas secrete the hormone(s) related to its cell(s) of origin. Some adenomas have no hormonal granules (i.e., null cell adenoma) or may have increased mitochondria (i.e., oncocytoma). Prolactinomas, the most common type of functional pituitary adenoma, can be found as part of the multiple endocrine neoplasia type I (MEN I) syndrome. Adenomas are thought also to develop as a result of untreated Addison’s disease, congenital adrenal hyperplasia, previous hypothyroidism, or hypogonadism. Pituitary changes associated with aging are seen, such as a diminished capacity to adapt to salt restriction or salt load with age. Basal levels of vasopressin are increased, but volume–pressure stimulation is decreased and kidney responsiveness may also be reduced.

GENETICS

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Understanding of human genetics is growing exponentially. Genes determine basic human form and function, and it is becoming increasingly evident that genetic abnormalities contribute at least in part to most disorders. Genetic information and knowledge are leading to earlier disease identification and improved treatment capabilities. Advances have allowed detection with a single blood test of diseases once identified by painstaking evaluation of family trees and subsequent chromosome analysis. Familiarity with and improved understanding of normal and abnormal human genetics have become critical to the practice of medicine because genetics plays an ever-increasing role in diagnosis, prevention, and management of disease. This chapter is an overview of human genetics. Described are patterns of genetic transmission and the molecular basis of genetic disorders. Principles of genetic counseling are presented. Common genetic malformations in otolaryngology are discussed as are the genetics of hereditary hearing loss and head and neck cancer.
DNA AND CHROMOSOMES
All genetic information is encoded by four bases composing molecules of deoxyribonucleic acid (DNA) (Fig. 2.1). Sequences of DNA, called genes, are transcribed into corresponding sequences of ribonucleic acid (RNA), which are translated into sequences of amino acids that constitute specific proteins. The proteins serve as structural components of cells and tissues or as enzymes that catalyze chemical reactions. The entire developmental program of an organism is effected by the precisely timed and orderly expression of genes. The human total DNA content, or genome, contains about 3 billion base pairs of DNA, which encode more than 80,000 functional RNA molecules and proteins (1).
Most of the human genome is contained within the nucleus of the cell, packaged into structures called chromosomes. Each somatic cell contains 46 chromosomes, the size and structure of which are the same for every person (Fig. 2.2). The nonsex chromosomes (autosomes) are represented in pairs, one inherited from each parent. The sex chromosomes are two X chromosomes in women and girls or an X and a Y in men and boys. Each chromosome consists of a single continuous DNA molecule. In addition to the nuclear genome, each mitochondrion contains several copies of a circular DNA molecule of approximately 16,500 base pairs. The mitochondrial DNA encodes some of the proteins involved in oxidative phosphorylation, transfer RNA (tRNA), and ribosomal RNA (rRNA). Mutations in mitochondrial DNA account for a set of diseases with a distinctive pattern of maternal transmission.
A preliminary map of the human genome has been completed through the coordinated efforts of the Human Genome Project. The ability to identify genes responsible for specific human disorders and provide tools for diagnosis is of great clinical importance (1). Ethical issues regarding discrimination, privacy, and ownership of genetic information have been raised.
PATTERNS OF GENETIC TRANSMISSION
Genetic disorders occur sporadically, as is typical of chromosomal anomalies and mutations that are genetically lethal, or they are transmitted from generation to generation. The classic patterns of genetic transmission include autosomal recessive, autosomal dominant, and X-linked.
Several terms are used to describe patterns of genetic transmission. The constitution of a particular genetic locus is called the genotype of the cell or organism. The particular forms of a gene on each chromosome are alleles. Persons who carry two identical alleles at a gene locus are said to be homozygous. Those who carry two different alleles (e.g., one normal and one mutant) are heterozygous. The observable characteristics of a cell or organism that are controlled by a particular genetic locus are called the phenotype.
Autosomal Recessive Inheritance
A prototypic pedigree for a family with an autosomal recessive disorder is illustrated in Fig. 2.3A. Autosomal recessive traits are expressed only if both copies of a gene are affected by mutation, that is, they are homozygous. Both parents usually are heterozygous, each having one normal copy of the gene and one mutant copy. Because each carrier parent has a chance of one in two (50%) of passing the mutant gene to any child, the risk of a child’s receiving the mutant gene from both parents and having the recessive trait is one in four (25%). Siblings of affected persons have a 67% risk of being carriers, but their risk of having affected offspring themselves generally depends on the frequency of the mutant gene in the population. Heterozygotes usually display no phenotypic effects of carrying the mutant allele. Autosomal recessive traits that are lethal before childbearing age, such as Tay-Sachs disease, generally occur within sets of siblings, and there is no evidence of the disorder in previous generations. Such traits also tend to occur more commonly in families in which the parents are consanguineous.
Many autosomal recessive disorders are more frequent in specific racial or ethnic populations. This frequency represents the expression of a mutation present in one or a few of the founding members of a group (founder effect) and a tendency for marriages to occur within the same group. Autosomal recessive deafness, which is entirely consistent with a normal life span and normal reproduction, can be present in two generations if both deaf parents are homozygous for the same recessive form of deafness. Such marriages would cause deafness among all the children. It is more typical, however, for all children of such couples to have normal hearing, because there are many genetic causes of deafness, and most such couples have different genetic forms of deafness.
Hurler syndrome, or mucopolysaccharidosis (MPS) type I, is an example of an autosomal recessive trait for which the gene is well understood (2). Hurler syndrome is caused by a mutation in the a-L-iduronidase gene (IDUA) that causes production of a protein with absence of normal enzymatic activity. Heterozygotes retain sufficient enzyme activity to be healthy, but homozygotes cannot metabolize mucopolysaccharides, and these compounds are stored in many tissues. The Hurler phenotype is a progressive disease that includes corneal opacity, hearing loss, enlarged tongue, hepatosplenomegaly, joint contractures, and life-threatening respiratory, cardiac, and gastrointestinal complications. A different mutation in the same gene is the cause of Scheie syndrome, a less severe form of MPS (type V) without mental retardation, corneal opacity, or stiff joints. Because the enzymatic activity of the protein is low but not absent, the metabolic block is incomplete. Persons who are compound heterozygotes, with one MPSI allele and one MPSV allele, have an intermediate phenotype, called Hurler-Scheie syndrome. There are many different mutations within the DNA sequence of the gene. Each is associated with a specific reduced activity of the enzyme. Today it is understood that most affected persons who are not the product of consanguineous matings are compound heterozygotes for two different mutations of the IDUA gene and that the phenotype (Hurler, Scheie, or Hurler-Scheie) depends on the combined enzymatic activity of the enzyme products of the two IDUA alleles.
Autosomal Dominant Inheritance
Unlike autosomal recessive inheritance, autosomal dominant traits are expressed in heterozygotes, who have a 50% chance of passing the mutant gene from generation to generation (Fig. 2.3B). For this reason, such traits are expressed by members of each successive generation. Both sexes can be affected, and men and women have an equal chance of transmitting the gene to the next generation. Both parents of a child with an autosomal dominant disorder should be examined for signs of the condition. If neither is affected, the recurrence risk depends on the rate of penetrance of the disorder. In a disorder with complete penetrance, a child may be affected sporadically because of new mutation, which conveys a low risk of recurrence for the parents.
Classic autosomal dominant traits, such as neurofibromatosis type 1 (NF1), may exist in a family for many generations. In some instances, the person affected by the autosomal dominant trait appears to be the only affected member of the family. One explanation is nonpenetrance, which is the apparent lack of phenotypic effect of a gene in a known carrier. NF1 is typical of many autosomal dominant traits in that its expression varies among individuals. About 60% of persons older than 20 years who carry the NF1 gene have cutaneous neurofibromas, 17% have scoliosis, 13% have optic glioma, and 97% express five or more cafe-au-lait spots by 20 years of age. Many other features are associated with this syndrome. Therefore the penetrance of the gene approaches 100% if the entire spectrum of the phenotype is considered. Nevertheless, about 50% of patients with NF1 appear to have no family history of the disease and probably do have new mutations. This apparently high rate of mutation in the NF1 gene may be accounted for partly because the gene is large and perhaps because segments of the gene sequence are predisposed to mutation, especially during spermatogenesis.
Sex-linked Inheritance
Traits expressed by genes on the X or Y chromosome are called sex-linked. Most sex-linked disorders among humans involve genes on the X chromosome. Because a father transmits a Y chromosome to his son, X-linked traits are not passed among male family members. A woman who carries an X-linked recessive disorder has a 50% chance of transmitting the condition to each son and a 50% risk of transmitting carrier status to each daughter (Fig. 2.3C). Rare X-linked recessive disorders, such as Duchenne muscular dystrophy, occur mostly among male carriers, who express only the mutant gene because they have only one X chromosome. Female carriers are heterozygous and usually do not manifest the disorder.
X-linked Kallmann syndrome is caused by a mutation that results in a deficiency of hypothalamic gonadotropin-releasing hormone. The responsible gene, KAL, was localized to the distal short arm of the X chromosome (band Xp22.3). The protein product of the gene appears to act during embryogenesis as a cell adhesion molecule responsible for normal neuronal cell migration (3). Boys with Kallmann syndrome have hypogonadotropic hypogonadism, micropenis, cryptorchidism, unilateral renal agenesis, and other defects. They also have complete, or nearly complete, anosmia due to agenesis of the olfactory lobes, so a simple test for this disorder is the University of Pennsylvania Smell Identification Test balanced with ammonia testing, which is sensed through cranial nerve V, not cranial nerve I. Effective hormonal therapy for hypogonadism and infertility is available. There also are autosomal dominant and autosomal recessive forms of Kallmann syndrome with variable expression of the anosmia, and there is variable expression of the phenotype among women and girls. X-linked dominant traits can be expressed by both sexes. In some cases, the effects among boys are so severe as to be incompatible with survival.
Multifactorial Inheritance
Many traits appear to cluster in families but do not display the transmission expected for a single-gene dominant or recessive trait. An example is cleft lip, which is a relatively rare, sporadic trait. Although recurrence in families occurs far less often than would be expected by the rules of mendelian inheritance, the risk of recurrence in a family with one affected child is greater than the population risk. Monozygous (identical) twins are more frequently concordant for the trait than dizygous (fraternal) twins, suggesting that inheritance plays some role in the disorder. Such traits are said to be subject to multifactorial inheritance, meaning that many factors, including several distinct genes and environmental factors, contribute to the trait. Quantitative attributes, such as height, are believed to be controlled by multifactorial inheritance. Congenital malformations, such as cleft lip and neural tube defects, are explained by the threshold model of multifactorial inheritance, in which a combination of genetic and nongenetic factors add to create a “liability” for the malformation (Fig. 2.4). The malformation occurs only if the liability exceeds a threshold value. The theory of multifactorial inheritance explains many sporadic congenital malformations. Families in which a known multifactorial disorder has occurred usually are counseled with empiric recurrence risk data.
Chromosomal Anomalies
The disorders discussed earlier are caused by mutations of single genes. Other disorders simultaneously involve several genes. The most extreme examples are disorders in which there are extra copies of an entire chromosome. The best known is Down syndrome, produced by an extra copy of chromosome 21. Other chromosomal abnormalities compatible with live birth include trisomy of chromosomes 13, 18, X, and Y (4). Chromosome loss is less well tolerated and usually causes death in utero. The apparent exception is the 45,X karyotype (Turner syndrome), but even here, most 45,X conceptions do not survive to term. The population incidence of Turner syndrome is approximately 1/3,000, and many of these individuals are mosaic, having a 46,XX or other cell population in addition to the 45,X cell population. Most abnormalities of chromosome number occur sporadically as a result of errors of chromosome segregation during meiosis.
Another mechanism of chromosomal anomaly is rearrangement, which includes deletion, duplication, translocation, or inversion. Deletions and duplications tend to have widespread phenotypic effects, including mental retardation, growth retardation, and multiple unrelated congenital malformations. The phenotypic effect depends on the specific genetic material gained or lost and the extent of gain or loss. In general, a gain of 1% or a loss of 0.5% of the genome is consistent with viability and can occur in a balanced configuration, in which there is no net loss or gain of material. Persons with balanced translocations or inversions usually are phenotypically normal but have a risk of transmitting an unbalanced chromosomal constitution to offspring. The result is familial transmission of a disorder of multiple congenital anomalies.
A microdeletion syndrome is caused by duplication or deletion of a small segment of chromosome material that contains a small number of few genes, which are functionally unrelated but by chance are linked together on the chromosome. The phenotype may vary because of different breakpoints, making delineation of a clear syndrome difficult (5). Affected persons usually appear sporadically, but familial clusters are known and typically are caused by a balanced chromosome rearrangement that runs in the family. Before the chromosomal basis was understood, such conditions were thought to represent autosomal recessive or new dominant mutations (6).
An example of a microdeletion syndrome of interest to otolaryngologists is velocardiofacial syndrome. This is a heterogeneous disorder usually caused by a microdeletion in chromosome 22, band 22q11.2 (Fig. 2.5) (7). Other dysmorphology syndromes known to be associated with the same microdeletion include DiGeorge and, at least occasionally, CHARGE (coloboma of the iris, heart disease, atresia of the choanae, retarded growth and development, genital and ear anomalies) and 3C (craniocerebellocardiac), Bernard-Soulier, Opitz G and BBB, and Cayler cardiofacial syndromes. The phenotype is variable, but the diagnosis usually is made when the constellation of a conotruncal heart defect and other malformations, such as hypocalcemic seizures and hypoplasia of the thymus and parathyroid glands of DiGeorge syndrome, is present. Hearing loss is a frequent associated finding. The deletion sometimes is familial, appearing in pedigree analysis as an autosomal dominant disorder with variable expression. The proband typically is the more severely affected person, and some family members have only one feature of the phenotype, such as ventricular outflow or aortic arch malformation. It has been estimated that 15% to 20% of such cases are associated with this microdeletion of chromosome 22 (7).
The velocardiofacial syndrome deletion usually is not detected with classic chromosome analysis methods. For this reason, it is important to involve a dysmorphologist familiar with such conditions and who can request the specific cytogenetic test to establish the diagnosis.
NONTRADITIONAL PATTERNS OF INHERITANCE
Several nontraditional patterns of genetic transmission have been recognized in recent years. One is maternal inheritance due to transmission of genes in mitochondrial DNA. The entire mitochondrial DNA complement of a child is inherited from the mother. Mutations in mitochondrial genes therefore are transmitted from a mother to all her children. Because mitochondria are excluded from sperm, the father does not pass a mitochondrial mutation to any child. Characterized mitochondrial disorders include Leber hereditary optic atrophy and encephalomyopathy ( and at least two genetic forms of isolated deafness (9).
Another nontraditional inheritance pattern is dynamic mutation, or unstable trinucleotide repeats, which is responsible for several forms of neurodegenerative ataxia and a few other disorders (Table 2.1) (10). Some segments of DNA normally comprise 20 or more repetitions of a three-base sequence, such as CAG or CGG. Some persons have more copies, which can cause instability during gametogenesis and production of offspring who carry very long repeats. In some conditions, the number of repeats in an affected person is about double the normal number, and in other conditions, the number of repeats exceeds 1,000. Although the inheritance pattern of these conditions behaves in many respects as a simple mendelian trait, mostly autosomal dominant, several features set them apart. Expansion of the DNA repeat usually is more likely in either spermatogenesis or oogenesis, leading to differences in phenotype, depending on which parent carries the mutation. The severe congenital form of myotonic dystrophy occurs only among offspring of affected mothers because expansion occurs preferentially during oogenesis. In fragile X syndrome, expansion likewise is limited to oogenesis, so daughters of unaffected men who transmit fragile X syndrome never are affected, whereas some sons and daughters of carrier women are affected. In Huntington disease, large expansions are transmitted preferentially by the man during spermatogenesis. The exact mechanism for this parent-of-origin effect in dynamic mutations is not well understood but has been postulated to reflect selection against expanded repeats during gametogenesis (11). Once a DNA repeat begins to expand in length, expansion can continue with each succeeding generation. This dynamism of the trinucleotide repeat sequence explains a phenomenon known as genetic anticipation, whereby the age at onset of the disorder is younger with each succeeding generation and is accompanied by a more severe phenotype.
A third type of genetic disorder is associated with the phenomenon of genetic imprinting (12). For most genes, both copies are genetically active. For other genes, however, only the maternally or the paternally inherited copy is genetically active. Each of these genes is imprinted during either paternal or maternal gametogenesis. Maternal and paternal imprints can be recognized from their DNA methylation patterns, usually involving a cytosine-guanine (CpG) DNA base sequence. Once it is set, the methylation imprint can be faithfully maintained during mitosis by means of postreplication methylation. The imprint is erased only when someone of the opposite sex transmits the gene.
The classic examples of syndromes that exhibit imprinting are Prader-Willi and Angelman syndromes. Both Prader-Willi syndrome and Angelman syndrome usually are associated with microdeletions of the region 15q11 to 15q13. Specific segments within this region are responsible for each syndrome, but an imprinting defect is demonstrated by the fact that a deletion of paternal origin causes Prader-Willi syndrome, whereas an otherwise identical deletion of maternal origin causes Angelman syndrome. Studies of DNA methylation patterns show that some genes in region 15q11-q13 are imprinted during oogenesis and that other genes are imprinted during spermatogenesis. A person must have one paternally and one maternally inherited chromosome 15 to ensure normal expression of all genes in this chromosome region. A microdeletion of paternal chromosome 15 causes Prader-Willi syndrome, and microdeletion of maternal chromosome 15 causes Angelman syndrome. Some patients with Prader-Willi syndrome and Angelman syndrome do not have a microdeletion. Some of these persons demonstrate uniparental disomy, whereby both chromosome 15s are inherited from the same parent. This has the same effect as deletion of one of the genetic imprints. Errors in the imprinting process also can cause lack of normal gene expression. In rare instances, persons with familial Angelman syndrome have normal methylation patterns. These patterns probably involve a point mutation in the imprinting control region of the gene or genes responsible for the Angelman syndrome phenotype, and the inheritance pattern is autosomal recessive (13).
GENETIC DISEASE MAPPING
The profound effect of molecular genetics on clinical practice is the result of the ability to identify genes responsible for specific disorders among humans and to provide tools for diagnosis. Completion of a first draft of the human genome sequence is vital to accelerating the process of gene identification. The basic technology is gene cloning (Fig. 2.6). Segments of human DNA, which may represent random fragments of the genome or may correspond to specific expressed genes, can be inserted (cloned) into bacterial, viral, or yeast DNA and grown in culture. A single bacterial or yeast colony that has incorporated a piece of human DNA of interest can be isolated. Gene libraries that incorporate fragments of the human genome or that incorporate DNA copies of messenger RNA (cDNA) can be made. The cDNA libraries represent only these genes expressed in a particular cell type and are useful for cloning functional genes.
Identification of genes involved in clinical disorders has proceeded in several phases. The first genes to be cloned were those for which the protein product was already known, including globin genes (e.g., sickle cell disease, thalassemia) and enzymes (e.g., phenylketonuria or Hurler syndrome). As genomic tools became further refined, a second approach, positional cloning, became possible. This began with mapping the disease gene, usually by means of tracking the segregation of the disease gene through a family in relation to genetic markers that had already been mapped (linkage analysis). DNA was isolated in this region and examined for mutations among affected persons. This approach has seen major success in identification of genes for conditions such as Duchenne muscular dystrophy, cystic fibrosis, NF1, and NF2.
With the gene sequence available, a candidate gene approach is increasingly used. The location of the disease gene is determined, usually by means of linkage analysis. Then genes known to reside in the region are examined for mutation. The procedure starts with the most plausible candidates based on patterns of expression or the physiologic roles of the gene products.
Identification of a gene responsible for a clinical disorder is a scientific advance. Diagnostic tools can be developed, and gene therapy becomes possible in some cases. Most important, the physiologic basis of the disorder becomes amenable to study, and the way is opened to develop pharmacologic approaches to treatment.
MOLECULAR DIAGNOSIS OF HUMAN GENETIC DISORDERS
In keeping with the interesting variety of gene expression, a diversity of mutations, such as base substitutions, insertions, deletions, and chromosomal rearrangements, can produce genetic disorders among humans. A single disorder typically is caused by many different kinds of mutations of the same gene in different persons (Fig. 2.7). A mutation classically is thought to involve the coding region of a gene in which mutations of one or a few nucleotides produce an abnormal protein or loss of the protein. Mutations in the noncoding regions of the gene, such as the promoter region, splice sites, and termination and polyadenylation signals, also can produce abnormal proteins or reduced levels of normal proteins. Structural rearrangements (insertions or deletions) involving several nucleotides to thousands of nucleotides can produce aberrant proteins or result in absence of proteins (14).

Because the causes of many genetic disorders have been elucidated and the genetic map is more complete, it has become increasingly possible to use molecular genetic approaches for diagnosis. Such approaches allow precise definition of whether a person has inherited a mutant gene, often before appearance of the disease phenotype, and can provide the basis of prenatal diagnosis. Two approaches are used—direct detection and indirect detection (linkage analysis) of abnormal genes.
Direct detection of a mutation is possible if the responsible gene is cloned and a limited number of mutations are known to cause the disease. Most molecular diagnostic tests rely on amplification of a target sequence with a polymerase chain reaction (PCR) (Fig. 2.8). Short sequences of single-stranded DNA (15 to 30 bases called oligonucleotides) homologous to sequences on the opposite strands of genomic DNA serve as the flanking regions for amplification of a DNA fragment of interest. The genomic DNA is denatured into single strands by means of heating, and the synthetic oligonucleotides are allowed to anneal and serve as starting points for a DNA synthesis reaction. This process is repeated sequentially. The result is exponential synthesis of new DNA that corresponds to the region bounded by the two oligonucleotides. PCR technology has revolutionized study of the human genome, including typing of genetic markers, mutation screening, detection of point mutations, cDNA and genomic DNA cloning, genome walking, DNA sequencing, and in vitro mutagenesis (14). A variety of strategies are used to identify mutations. They range from complete gene sequencing to approaches that target a specific single-base change (Table 2.2).

If the disease gene is not cloned but linkage has been established between the disease locus and marker genes, or if the gene has too many defects, making direct analysis impractical, linkage studies can be used for diagnosis in some families. Minor variations of base sequence, polymorphisms, are common among humans. Most of these variants are not located in coding regions of genes and herefore are not responsible for phenotypic effects; however, they can be detected by means of PCR or Southern blotting and constitute heritable markers that can be tracked with a disease trait within a family. The DNA markers do not correspond to molecular defects within a gene but merely tag a disease-bearing chromosome as it is inherited. The use of linkage analysis in the diagnosis of a genetic disorder is illustrated in Fig. 2.9. Although it is a powerful approach, genetic linkage is subject to diagnostic error and is not possible for all families. Diagnostic error is caused by genetic recombination during meiosis, which can change the association of a particular marker allele with a disease allele, by misattributed paternity, or by genetic heterogeneity (diseases that look phenotypically identical but are caused by defects in different genes, such as Alzheimer disease). The technique can be used only by families in which there is a clear pattern of mendelian transmission, for which the clinical diagnosis implicates the linked disease gene unequivocally, and in which the persons who carry the disease gene are heterozygous for the marker, allowing the two chromosomes to be differentiated.
GENE THERAPY
Knowledge of the structure of a gene responsible for a genetic disorder can lead to improved therapy through earlier diagnosis. In addition, the disorder can be managed prospectively with classic treatments or new knowledge of pathogenesis gained from study of the gene product. The long-term hope for genetic therapy is to replace a defective copy of a gene in the cell and reverse the effects of the mutation. There are a number of ways of introducing foreign genes into cells and obtaining stable expression of these inserted sequences. Human gene therapy is being attempted in experimental settings for diseases such as cystic fibrosis, Duchenne muscular dystrophy, familial hypercholesterolemia, and cancer. There are many biologic obstacles to overcome, including obtaining sustained levels of expression comparable to those of normal cells, and targeting the inserted genes to the appropriate cell type. Currently more than 200 gene therapy protocols have been approved for treatment of patients with cancer, acquired immunodeficiency syndrome, and genetic diseases (15).
There are four general strategies in gene targeting. In one method used when there is a loss of normal gene function, extra copies of the normal gene are introduced into cells. This method can be effective in the management of autosomal recessive disorders, such as cystic fibrosis. In one study, investigators used adenovirus vector to introduce wild type p53 tumor suppressor gene into malignant tumors of the head and neck. A favorable response occurred with regression or stabilization of disease for 3.5 months among one half of the patients tested (16).
Targeted killing of specific cells is a second approach often used in gene therapy for cancer. In this approach, the inserted gene produces a lethal toxin that kills the target cells, encodes a gene that is sensitive to a certain administered drug, or stimulates the immune system to kill the target cells. Studies are under way in which a plasmid vector is used to introduce major histocompatibility complex HLA-B7 into squamous cell carcinoma of the head and neck and thereby induce immunologic killing of the cancer. Preliminary studies show a 20% to 25% response rate (15).
A third approach to gene therapy is to correct the mutation either at the DNA level (homologous recombination) or at the RNA level (ribozymes). The final approach is targeted inhibition of gene expression at the DNA, RNA, or protein level, such as use of antisense genes. This fourth approach may be yield important techniques for managing many types of cancer and infectious diseases (14).
TREATMENT OF PATIENTS WITH GENETIC DISORDERS
The American Society of Human Genetics has defined genetic counseling as a “communication process which deals with . . . the occurrence or risk of occurrence of a genetic disorder in a family” (17). The process includes helping the family to (a) understand the medical facts, including the diagnosis and course of the disorder, (b) appreciate the role of heredity in the disorder, including knowledge of the risk of recurrence, (c) understand the options available to deal with the risk of recurrence, (d) choose a course of action, and (e) make the best possible adjustment to dealing with the disorder and the choices they make.
Correct diagnosis is key to caring for patients with inherited disorders. Many disorders can appear similar clinically and yet be distinct genetically. Moreover, many genetic disorders have pleiotropic effects. A pedigree should be constructed for the family, similar to that shown in Fig. 2.3 to help recognize the pattern of transmission or determine that a disorder is sporadic.
A difficult challenge in genetic counseling is posed if a child has a problem for which a specific diagnosis cannot be made. Most often, this occurs when a child has congenital malformations that do not fit a particular syndrome. It is always wise to examine these children for chromosomal anomalies. At most institutions, an experienced dysmorphologist or medical geneticist is available for consultation. If the chromosomes are normal, it may be impossible to establish a specific cause. In this case, counseling must take into account the possibility that the disorder has a genetic basis and that recurrence is possible. Although the recurrence risk cannot be quantified in this situation, empiric recurrence risk may be available. The family needs to understand that the lack of a specific diagnosis or family history of the disorder does not preclude that the problem is genetic and that recurrence is possible.
There are several options for dealing with risk of recurrence. Options likely to be agreeable to a family depend on factors such as their perception of the severity of the disorder, whether the disorder can be managed or be diagnosed prenatally, and the ethical and religious beliefs of the family. Prenatal diagnosis, usually by means of amniocentesis or chorionic villus sampling, is widely accepted and is available for cytogenetic disorders and for an ever-increasing number of mendelian and nontraditionally inherited conditions. Modalities for prenatal diagnosis includes level III ultrasound examination, which can be used to detect some of the congenital malformations associated with many syndromes.
Prenatal diagnosis is undertaken for several reasons. The most obvious is consideration of pregnancy termination if a fetal anomaly is found. Other couples choose prenatal diagnosis to allow planning for the medical needs if a child has an inherited disorder. Prenatal surgical procedures can be performed for some anatomic defects. A major canon of genetic counseling is to be nondirective. The counselor must present options in a neutral manner, not allowing his or her opinions to influence a couple’s decision. Having a child with an inherited disorder imposes many practical and emotional stresses on a family. Complex medical decisions may have to be made and a substantial financial burden sustained. The disorder may be life threatening or may lead to chronic illness and developmental impairment. On the other hand, a familial condition to which adaptation is readily achieved, such as deafness, may not be considered a burden by the family. The correct diagnosis may be of interest only in terms of the likelihood of having children who share the trait of deafness and in terms of monitoring for associated problems such as nephritis.
The medical issues can dominate all other issues for a family. Health professionals can ease the burden by providing competent care, providing information in an understandable manner, and maintaining open communication with the family and the other health care professionals. The geneticist can play a special role by addressing the question of cause. It is especially important to take a thorough family and pregnancy history. It is rare to identify a specific environmental exposure that caused a child’s problems, but it is routine to learn that a family member is worried that an insignificant event might have contributed. These concerns usually are disclosed only after directed questioning. After recognizing the source of anxiety, the counselor or physician can reassure a family and help them deal more directly with the medical and emotional issues at hand.
GENETICS OF OTOLARYNGOLOGIC DISORDERS
A large number of otolaryngologic disorders are known to be familial or to have a genetic component. Although the details of these disorders are discussed elsewhere, some of the more important are described herein to highlight the genetic issues raised.
Congenital Malformations
A variety of congenital malformations affect the ear, nose, and throat. Some occur as a component of multiple congenital malformation syndromes, which may be caused by single-gene mutations or chromosomal abnormalities. Others occur sporadically, displaying multifactorial inheritance. A classic example is cleft lip, which occurs in isolation or with cleft palate. Although facial clefts usually occur sporadically, they can be a component of mendelian disorders or occur in association with multiple congenital anomalies. This is also true of anomalies such as preauricular pits or malformation of the external ear.
Kartagener Syndrome
Kartagener syndrome is an autosomal recessively inherited condition of dextrocardia, situs inversus, immotile sperm, anosmia, bronchiectasis, and chronic cough, all secondary to absence or malformation of the dynein arm structures of cilia.
Down Syndrome
Down syndrome, or trisomy 21, is the most common malformation syndrome and occurs in increasing frequency with increasing maternal age. Common otolaryngologic manifestations include upslanting palpebral fissure, low nasal bridge, macroglossia, narrow palate, protruding tongue, and atlantoaxial instability.
Craniosynostosis
Apert syndrome involves craniosynostosis, syndactyly and midfacial malformations, and mental retardation. Most cases are sporadic mutations. Crouzon syndrome involves craniosynostosis, maxillary hypoplasia, and proptosis. Intelligence is normal. These syndromes are transmitted in an autosomal dominant pattern.
Treacher Collins Syndrome
Treacher Collins syndrome or mandibulofacial dysostosis is characterized by a hypoplastic mandible and maxilla, hypoplastic supraorbital rims, narrow face, depressed cheek bones, bizarre inferiorly placed pinnae, downslanting palpebral fissures, and normal intelligence. The inheritance pattern is autosomal dominant.
Hereditary Deafness
Both congenital and acquired forms of deafness can have a genetic basis (9). One in every 1,000 infants is born with hearing loss. By the age of 80 years, more than 50% of persons have some degree of hearing loss (18). As environmental and infectious causes of hearing loss are being controlled, it is estimated that more than 60% of congenital hearing impairment is genetic and that one third to one half of all deafness has an inherited component (18). Hereditary hearing impairment (HHI) can be classified as syndromic or nonsyndromic (9,18). Syndromic hearing loss (30% of all HHI) occurs in association with other anomalous phenotypic features. Craniofacial malformations, renal abnormalities, skeletal dysplasia, and pigmentary anomalies are some common examples. Nonsyndromic hearing loss (70% of all HHI) occurs as an isolated deficit. Since approximately 1990, positional cloning techniques have allowed rapid identification of a number of single genes that cause nonsyndromic hearing loss.
Syndromic Hearing Loss
Hundreds of autosomal dominant, recessive, and X-linked forms of syndromic hearing loss have been described. Molecular genetic studies have revealed the locations of genes responsible for some of these syndromes. Waardenburg syndrome is a dominantly transmitted disorder that includes sensorineural hearing loss, dystopia canthorum (widely spaced inner canthi), and a disorder of neural crest migration. Intrafamilial heterogeneity in the phenotype (called variable expressivity) exists. PAX3, a gene on the long arm of chromosome 2, has been found to be mutated in many persons with Waardenburg syndrome (19). About 83% of persons who carry the gene have penetrance, that is they have physical manifestations. Dystopia canthorum, heterochromia, or white forelock occurs among approximately one third of gene carriers and deafness among approximately 25% (20).
Another genetically heterogeneous disorder associated with hearing loss is Usher syndrome. In Usher syndrome type I (USH1), partial sensorineural hearing loss occurs with development of retinitis pigmentosa after the first decade of life (21). Families with Usher syndrome type II (USH2) have congenital deafness and early onset of retinitis pigmentosa. Five distinct Usher syndrome genes have been mapped to chromosome bands 1q32 (USH2), 14q32 (USH1), 3q21 (USH3, the Finland variety), 11p15 (USH1C, the Acadian variety), and 11q13 (USH1B) (22).
Pendred syndrome is an autosomal recessive disorder associated with goiter and an increased risk of thyroid carcinoma. It has been mapped to the long arm of chromosome 7. There is variability in expression of the gene defect within families. Some members have near-normal hearing, and some have unilateral deafness. Another mutation in the gene responsible for Pendred syndrome may be responsible for one form of autosomal recessively inherited nonsyndromic deafness (23).
Deafness and nephritis occur together in many conditions. Alport syndrome, for example, is characterized by nephritis, deafness, and cataracts and can be inherited in an X-linked or an autosomal pattern. Mutations in various collagen protein genes are responsible for most forms of Alport syndrome, including the a-5-collagen gene, which is located in the short arm of the X chromosome (24), and genes that code for collagen IV subunits, which have been mapped to chromosome 2 (25).
Nonsyndromic Hearing Loss
Since approximately 1995, linkage analysis has accelerated mapping of genes that cause monogenic nonsyndromic hearing loss. Monogenic prelingual hearing loss is approximately 75% autosomal recessive, 20% autosomal dominant, 5% X-linked, and less than 1% mitochondrial (9). Two parents with autosomal recessive deafness can have children with normal hearing because the mutant gene may be different in each parent. By 1999, 44 gene loci on 19 chromosomes and 15 genes, including two mitochondrial genes, for nonsyndromic hearing loss had been identified (Table 2.3) (9). These loci are labeled DFN (for deafness). DFNA designates autosomal dominant loci; DFNB designates autosomal recessive loci; DFN are the X-linked recessive loci (9). Protein products of these deafness genes include transcription factors, myosin, connexin (involved in formation of cell membrane channels), formin (involved in maintenance of the inner ear cytoskeleton), ion transporters, structural proteins of the organ of Corti, and extracellular matrix proteins. Mitochondrial genes responsible for monogenic nonsyndromic hearing loss include the gene for 12S rRNA and the serine tRNA (9,18).
DFNB1 mutation (connexin-26) on chromosome 13q12 was the first cloned gene to be implicated in and is the most common cause of nonsyndromic hearing loss. It accounts for approximately one half of all cases of autosomal recessive prelingual hearing loss and 20% of all prelingual deafness (9). The hearing loss is moderate to profound but stable. Connexin encodes cell plasma membrane channels involved in intercellular exchange of ions and small molecules. Approximately 1% to 3% of white persons carry a DFNB1 mutation. Molecular screening is possible for connexin 26 abnormalities as part of the diagnosis of hereditary prelingual deafness (9,18).
DFNA9 (the COCH gene) on chromosome 14q11-13 is the gene most frequently involved in autosomal dominant postlingual hearing loss. Clinical features include progressive hearing loss starting in the high frequencies and variable vestibular symptoms. COCH is believed to encode an extracellular matrix protein. Deposits of mucopolysaccharides have been found in the inner ears of patients with the DFNA9 mutations.
DFN3 (encoding the POU3F4 gene), located on chromosome Xq21, is the most common X-linked locus involved in nonsyndromic hearing loss. Hearing loss is progressive with fixation of the stapes footplate. POU genes encode transcription factors. POU3F4 is expressed in the mesenchyme of the inner and middle ear, where it is involved in maturation of bone (9).
The most frequent form of mitochondrial hearing loss involves mutation of the 12S rRNA gene. This mutation occurs in association with aminoglycoside ototoxicity. The mutated rRNA is likely more similar to bacterial rRNA, the target of aminoglycoside antibiotics. Progress in identifying nonsyndromic HHI genes will clarify the underlying molecular mechanisms of hearing and hearing loss, improve genetic counseling, and lead to development of specific therapies for hearing loss.
Genetics of Head and Neck Cancer
Cancer of the head and neck accounts for about 5% of all deaths of cancer in the United States (26). Since approximately 1980, innovations in standard surgical treatment, radiation therapy, and chemotherapy have resulted in only modest improvements in survival from squamous cell carcinoma of the head and neck. The goal of research directed at understanding the basic genetic mechanisms of head and neck cancer is to increase the survival rate among persons with cancer of the head and neck.
Most malignant tumors among humans develop in a complex interaction between genetic and environmental factors. At the most basic level, all cancers are genetic in that development and progression occur because of accumulation of chromosomal and genetic mutations. Four basic relationships can be identified: persons with genetic predisposition for cancer but no environmental exposure, persons with environmental exposure but no genetic predisposition, spontaneous mutations among persons who have neither genetic predisposition nor environmental exposure, and persons with both genetic predisposition and environmental exposure (27). There has long been evidence that squamous cell carcinoma of the head and neck may have a genetic basis despite the existence of known and multifactorial environmental influences (27,28 and 29). In families with smoking-related malignant disease, genetic analysis supports an autosomal dominant inheritance pattern (30). This genetic susceptibility also may explain why some persons with only mild tobacco or alcohol exposure have squamous cell carcinoma of the head and neck, whereas others with many times more use never do (27).
Loss or alteration of cell-cycle control is an intrinsic factor in the development of cancer. Tumor suppressor genes are genes that have been identified as having regulatory control of the cell cycle. When such regulatory forces are altered or lost because of mutational events, cell-cycle control is changed. Poorly regulated or prolific cell growth can occur, and cancers can develop.
Oncogenes are genes that have been causally identified with the development of cancer. An example is the RET oncogene. Germline mutations in RET, located on chromosome 10q11.2, have been identified in families that manifest hereditary medullary carcinoma of the thyroid (31). Identification of RET mutations is used as screening for multiple endocrine neoplasia type 2b and familial medullary carcinoma of the thyroid. Because early identification and management of medullary carcinoma of the thyroid markedly affect outcome and survival, genetic screening of patients and their close relatives has become a critical part of the diagnosis and management of medullary carcinoma of the thyroid. In most cancer types, both loss of tumor suppressor genes and oncogene activation occur. The former is believed to be more important than the latter for squamous cell carcinoma of the head and neck (32). Many of the known oncogenes and tumor suppressor genes are common to many cancers, and identification of a genetic abnormality in one tumor type often is relevant to others.
Some persons are more susceptible to cancer because they are heterozygous for a tumor suppressor or oncogene mutation. Because a single, inherited altered gene already is present in a diploid cell (one hit), only the remaining normal gene copy has to mutate for cancer to develop (two hits). Without the original hereditary abnormality, development of cancer is less likely because two acquired mutations would have to occur. This premise has been shown to be true for some cancers. Retinoblastoma occurs in both heritable and sporadic patterns. Sporadic retinoblastoma is unilateral (30). Persons with the hereditary form have loss or mutation and inactivation of a tumor suppressor gene called Rb1. These persons have a hereditarily determined single hit. The likelihood that retinoblastoma will develop is nearly 50%, and these lesions often are bilateral. Fifty percent of offspring are susceptible to the cancer. The RB1 tumor suppressor gene helps to regulate transcription of other genes and thus is involved in regulation of the cell cycle. Insertion of a normal RB1 gene can result in a return of normal cell regulation (33).
Cytogenetics has been used in the study of squamous cell carcinoma of the head and neck (34,35). Several chromosomal abnormalities have been identified. Oncogenes and tumor suppressor genes are presumed to be located at the breakpoints of these deletions, amplifications, and translocations. Common chromosomal abnormalities identified in squamous cell carcinoma of the head and neck include 3p-, believed to be an early chromosomal change in squamous cell carcinoma of the head and neck; 11q13 rearrangements, the location of the cyclin D1 oncogene (36); and 9p21-22, the site of cell cycle gene p16 (32). Loss of 18q is likely related to advanced disease and carries a poor prognosis (36,37). Other chromosomal losses include 5q, 8p, and 13q,17p. Amplifications include 3q, 5q, and 11q. Cancer cells can be haploid (half the normal DNA content), diploid (two times the normal DNA content), or tetraploid (four times the normal DNA content). Aneuploidy (abnormal DNA content) is a feature of many cancer cells. It is believed to be caused by altered proliferation of tumor cells and to reflect aggressive clinical behavior (38). Ploidy analysis, however, has not shown any prognostic factors and has done little to help identify the nature of head and neck cancer (38).
The cell-cycle gene most widely studied in relation to cancer among humans is the tumor suppressor gene p53, found on chromosome 17p. The p53 protein helps to control the cell cycle by binding with cyclin-dependent kinins to arrest cell replication in G1 (39). This allows the cell to repair any DNA damage or mutations that have occurred. If DNA repair fails, p53 can induce apoptosis or programmed cell death (36). Loss of activity of p53 results in an increase in the number of chromosomal abnormalities (40). This loss of p53 occurs in more than half of instances of squamous cell carcinoma of the head and neck. For patients with a p53 abnormality in the index tumor, p53 can be evaluated at the margins of the tumor at the time of resection. The presence of mutant p53 at the margins is predictive of recurrence, even if the margins appear normal at light microscopic examination (41). It is likely that the presence of p53 is related to early genetic changes in squamous cell carcinoma, such as the conversion of normal mucosa to dysplastic mucosa. Although p53 overexpression has been found to be predictive of a favorable response to chemotherapy and organ preservation protocols, p53 expression has not been found to be predictive of survival from squamous cell carcinoma of the head and neck (36).
Cyclin D1, located at chromosome 11q13, is the most frequently amplified protooncogene in squamous cell carcinoma of the head and neck. This oncogene product accelerates cell cycle progression. Overexpression correlates with advanced disease and reduced overall and disease-free survival rates (32). The p16 gene product is an inhibitor of cyclin pathways and cyclin D1 and therefore is involved in cell cycle regulation. Inactivation of p16 is one of the earliest genetic events in squamous cell carcinoma of the head and neck (32).
The bcl family gene products are involved in cell cycle regulation and apoptosis. The bcl-2 gene product inhibits apoptosis by blocking p53 dependent pathways. Overexpression of bcl-2 has been linked to resistance to chemotherapy. The bax gene encodes an inhibitor of bcl-2. Bcl-xL prevents apoptosis; bcl-xs promotes apoptosis (36).
Epidermal growth factor, epidermal growth factor receptor, and transforming growth factor a are growth factor gene products frequently overexpressed in squamous cell carcinoma of the head and neck. None has been shown to be a reliable prognostic indicator or tumor marker for recurrence (32).
Squamous cell carcinoma of the head and neck arises from a clonal population of cells that have acquired many genetic alterations in a several-step process (34). Unlike the colon cancer model, in which an orderly sequence of genetic events leads from adenoma to metastatic carcinoma (42), it is likely that the genetic mutations in squamous cell carcinoma of the head and neck do not necessarily follow one rigid sequence. Nonetheless, certain genetic changes are believed to occur early and can be found in dysplastic tissue. Others occur late and reflect invasive squamous cell carcinoma. A possible progression of genetic changes for squamous cell carcinoma of the head and neck is depicted in Fig. 2.10.
CONCLUSION
Advances in understanding human genetics allow more precise diagnosis of medical disorders. Molecular methods increasingly allow diagnosis before the appearance of symptoms or even prenatally. The possibility of genetic recurrence should be addressed in the management of any inherited disorder, and counseling should be offered. As knowledge of pathogenesis is gained, many genetic disorders may become amenable to therapy, either medically, through gene product replacement, or through novel means of gene manipulation.

ADVANCES IN MOLECULAR BIOLOGY

2009-02-07T06:33:00.001-10:00

The discovery of the DNA double-helix structure by Watson and Crick in 1953 was the most important step toward understanding genetics, protein regulation, and normal cell function. As technology advanced beyond the gross and histologic levels, the cell and its underlying genetic machinery became targets for exploration. It is well established that disease essentially begins at the gene level, and resulting aberrations in gene product expression are what are presented to clinicians. Molecular biology techniques developed for the detection and manipulation of proteins, RNA, and DNA are now commonly used in research directed at the diagnosis and understanding of an array of diseases. The field of hereditary deafness, for example, has benefited from the development of advanced genetic techniques. Further discoveries in the molecular pathogenesis of diseases will allow physicians to improve prevention, diagnosis, prognosis, and treatment. This chapter provides a brief description of recent advances in molecular biology within otolaryngology.
HEAD AND NECK CANCER
Cancer has long been suspected to be a disease ultimately caused by the loss of genetic control. In the last several years, many studies have identified genetic markers that can be used in the prognosis of cancers in the breast, lung, and other sites. The search for gene markers in head and neck cancer lagged. Recent studies have identified markers that may serve as prognostic factors in the management of head and neck cancer.
Normal cell life is regulated by specific genes that code for a variety of proteins that affect homeostasis. Alterations in genes that regulate cellular proliferation, differentiation, and apoptosis (programmed cell death) differentiate neoplastic cells from normal cells. Gene alterations can occur in several ways, such as genome damage by means of mutation or deletion, imprinting, chromosomal rearrangement, or mitotic recombination. Gene activity also can be affected by interaction with viral oncoproteins or carcinogens. In general, any such changes can cause aberrant gene expression and tumorigenesis.
The regulatory genes can be divided into two main categories. Protooncogenes encode proteins that stimulate cellular proliferation. In most cases, they code for growth factors, receptors, and other molecules involved in signal transduction pathways or for transcription factors that regulate gene expression. Oncogenes are protooncogenes that have a mutation that causes malignant transformation when they are inappropriately expressed. Tumor suppressor genes normally hinder the growth of uncontrolled cell proliferation driven by oncogenes. The double-hit theory of cancer development holds that both alleles of a tumor suppressor gene must be inactivated for the cell to proliferate. These abnormal cells thus are allowed to reproduce and expand unchecked.
Several gene regulators have been identified, particularly in regard to squamous cell carcinoma. The function of these genes typically is evaluated indirectly by means of detection of the associated gene product. Continued identification of specific genes, gene products, and their roles in tumor regulation may lead to new preventive techniques, improved diagnostic capabilities, reliable prognostic markers, and specific treatment strategies.
B-cell Lymphoma/Leukemia-2 Gene
The B-cell lymphoma/leukemia-2 gene (bcl-2) is a tumor-suppressor gene and primary regulator of apoptosis. Normal bcl-2 expression inhibits apoptosis and counteracts the effects of p53. The bcl-2 proteins are present predominantly in the mitochondrial membrane and have been found in a variety of tissues, including lymphoid tissue, bronchial epithelium, skin, intestine, breast, prostate, thyroid, and nasopharynx (1). Under healthy conditions, bcl-2 proteins are present only in the basal or proliferating cells of these tissues.
The expression of bcl-2 protein has been studied in tumors of the breast, lung, and prostate as well as in tumors of the head and neck. Although bcl-2 is a relative newcomer to the group of recognized gene markers, it is emerging as a marker of clinical significance. Numerous studies have been performed to identify other gene markers, such as p53, as prognostic indicators. None of the investigators found consistent, statistically relevant predictors of outcome.
In early studies, Friedman et al. (2) identified bcl-2 as a highly sensitive marker for predicting prognosis in early squamous cell carcinoma of the larynx. This was especially important because the group of patients who participated in the study included those treated with either radiation or surgery alone. In a retrospective study of early-stage squamous cell carcinoma of the head and neck (T1N0 or T2N0 glottic larynx; T1N0 oral cavity, pharynx, supraglottic larynx), overexpression of bcl-2 correlated with a significantly reduced cure rate, 50% versus 90%, which is expected in the management of these localized lesions. There was no significant difference in recurrence rate with regard to treatment modality (surgery or radiation therapy).
Other studies have shown similar results among patients treated with radiation only. Gallo et al. (3) conducted a study with a group of patients who had tumors of the head and neck at all sites; 70% of the tumors were located in the larynx. The investigators showed that overexpression of bcl-2 correlated with a shortened disease-free interval and decreased overall survival rate. These results are greatly encouraging but not conclusive. In a study involving 70 patients with squamous cell carcinoma of the larynx and several tumor markers identified, bcl-2 was not a prognostic discriminator (4). Additional studies by Friedman et al. (5) showed that bcl-2 is not a prognostic indicator in advanced laryngeal carcinoma.
Two mechanisms have been suggested by which disordered bcl-2 expression can cause resistance to treatment and shorter survival times. Overexpression of bcl-2 may prevent spontaneous apoptosis and lead to more rapid accumulation of tumor cells for a given proliferation rate. Spontaneous apoptosis is known to be an important factor in tumor-volume doubling time. Another possibility is that bcl-2 confers resistance to therapy by blocking treatment-related apoptosis. Radiation therapy and chemotherapy are directed at inducing apoptosis.
The prognostic significance of bcl-2 overexpression alone may not apply to all tumors. In one study, patients with squamous cell carcinoma of the lung and overexpression of bcl-2 had a better survival rate than those not expressing bcl-2 (6). A similar observation was reported for breast cancer (7). These contradictory findings may be the result of different methods of assessing bcl-2 expression, but the more likely explanation may involve the influence of other closely related gene products, such as bax, bcl-sl, bcl-xs, and bad (8). For example, bcl-2 is thought to function largely by means of antagonizing the cell death–inducing effect of bax. If bax expression is somehow impaired, cancer cells may be resistant to apoptosis even in the presence of very low levels of bcl-2. Abnormalities of bax expression have been documented for breast cancer (8). Assessing the family of related genes instead of bcl-2 alone in squamous cell carcinoma of the head and neck may make it easier to ascertain who will have a poor response to standard treatment.
p53
The p53 tumor suppressor gene is responsible for arrest in the cell cycle after genetic injury. It allows the cell to repair the DNA defect before the next cell division. The gene also induces apoptosis. Alteration in the p53 gene locus is the most commonly identified genetic mutation in squamous cell carcinoma of the head and neck and in all types of cancer among humans.
Mutations of p53 and overexpression of p53 protein have been found in approximately 40% of invasive squamous cell carcinomas of the head and neck and in more than 50% of malignant neoplasms of the mouth (9). Overexpression of p53 also has been observed in dysplasia and carcinoma in situ of the larynx (10). Cigarette smoking is known to cause p53 mutations (11). Squamous cell carcinomas with p53 mutations are more common among persons who smoke and among those who drink heavily. The mutations among these persons have been found over a broad area of the chromosome, rather than at limited sites, as is characteristic of spontaneous mutations in abstainers. Mutations of the p53 gene are less frequent among patients with squamous cell carcinoma who are older than 75 years than among those 40 to 70 years of age (12). This finding implies that squamous cell carcinoma of the upper aerodigestive tract among elderly patients may be a result of a longer period of exposure to genetic injuries from spontaneous mutation or environmental factors combined with an aging repair process. Koch et al. (12) found a loss of heterozygosity of markers on a number of chromosomal arms in specimens of squamous cell carcinoma. This finding indicated the possible involvement of several suppressor genes.
Overexpression of p53 has had mixed results as a prognostic factor. In a review of T1 squamous cell carcinoma of the floor of the mouth and ventral tongue, no statistically significant correlation was found between the level of p53 expression and tumor aggressiveness (13). In contrast, a review of oropharyngeal squamous cell carcinoma specimens showed that p53 protein was predictive of increased risk of death independently of tumor grade, stage, and lymph node status (14). Expression of p53 seems to correlate with a poor prognosis, particularly in advanced squamous cell carcinoma of the head and neck. The full negative effect of overexpression p53 may occur only very late in disease, thus correlating with survival in end-stage disease. The function of p53 protein can be interrupted with viral oncoprotein binding, such as the E6 protein of human papillomavirus types 16 and 18, and thus potentiate carcinogenesis (15).
Human Papillomavirus
Human papillomavirus (HPV) has been linked to development of papilloma in the nose and respiratory tract and to carcinogenesis in the genitourinary tract. Known oncogenic types 16, 18, and 31 have been found in squamous cell carcinoma of the tongue, tonsil, larynx, and pharynx. Human papillomavirus DNA was detected in 46% of archival tissue specimens of laryngeal and hypopharyngeal carcinoma, and the presence of this DNA appeared to correlate with a poorer prognosis than among cases in which there was no detectable HPV (16). Portugal et al. (17) detected HPV (11%) and p53 mutation (66%) within the same specimens of squamous cell carcinoma of the oral cavity and tonsil, which showed that neither p53 gene mutation nor HPV infection serves as a prognosticator of tumor behavior, although survival rates were higher among persons with HPV-infected cancer of the tonsil (17). Among patients with a history of low alcohol and tobacco use, HPV infection was an independent risk factor for squamous cell carcinoma of the oral cavity and tonsil.
The exact role of HPV in carcinogenesis in the upper aerodigestive tract is unknown. Binding of E6 HPV proteins to the p53 tumor suppressor gene may lead to gene product degradation and unchecked cell proliferation. The E7 HPV protein is known to form complexes with the retinoblastoma tumor suppressor gene product pRB, and this process leads to tumorigenesis (18). No role for the retinoblastoma gene has been found in squamous cell carcinoma of the head and neck. An association of HPV with mutated H-ras oncogene has been suggested in squamous cell carcinoma of the mouth (19). However, the ras oncogene group is infrequently involved in head and neck cancer (20).
Thyroid Cancer
Quantification of nuclear DNA in papillary carcinoma reveals a close correlation between DNA ploidy and the aggressiveness of thyroid lesions (21). Two groups of patients have been compared, one with noninvasive disease and another with invasion of the thyroid. Forty percent of invasive lesions were aneuploid, whereas all tumors without such extent were diploid. The thyroid has been considered an advantageous target for somatic gene therapy because of its great capacity for protein synthesis, high blood flow, and sensitivity to hormonal regulation. O’Malley et al. (22) developed a method for transferring genes into cultured human thyroid follicular cells with the use of retroviral vectors. Cells were transfected with either the LNL6 vector, carrying the gene for neomycin resistance, or the zen-B-gal vector, carrying the b-galactosidase marker. In this experimental model, transfection rates ranged from 0.1% to 3%.
Salivary Gland Neoplasms
The factors of prognostic significance for salivary gland neoplasms are well known and are based mainly on histologic features, including status of surgical margins, perineural invasion, and lymph node metastasis as well as histologic type and grade. In the future, prognostic indicators found at the gene level may provide the most accurate information. DNA ploidy was examined as a prognostic indicator for adenoid cystic carcinoma in a small series of 20 patients (23). All tumors with DNA aneuploidy recurred; only two of the 14 DNA diploid lesions recurred. These results may have an effect on treatment planning, particularly because DNA aneuploid tumors are more radiosensitive than are DNA diploid tumors.
Overexpression of c-erb-b2 oncoprotein, a receptor of growth factors, in adenocarcinoma of the major salivary glands may be an indicator of aggressiveness. In 59 cases of malignant tumors of the major salivary gland that also included squamous cell, adenoid cystic, and mucoepidermoid carcinoma, only adenocarcinoma produced a positive staining result (24). The tumors with c-erb-b2 overexpression were more difficult to resect, were associated with more frequent nodal metastasis, and resulted in a markedly lower disease-free survival than did adenocarcinomas that did not show overexpression.
OTOLOGIC DISEASE
Acoustic Neuroma
Acoustic neuroma accounts for about 8% of all intracranial tumors. These tumors are bilateral and familial in 4% of cases, a condition associated with neurofibromatosis type 2. The neurofibromatosis type 2 gene has been localized to chromosome 22. Genetic analysis of both familial and sporadic acoustic neuroma has revealed frequent loss of alleles at chromosome 22 in both types (25,26). Greater extent of chromosome 22 deletions was associated with larger tumor size, but this finding was not statistically significant. Further work is being directed at identifying a prognostic indicator for tumor aggressiveness.
Otitis Media
Clinical research suggests that susceptibility to microorganisms that cause acute otitis media may be hereditary. Kalm et al. (27) tested for several human lymphocyte antibody (HLA) antigens in patients with recurrent acute otitis media. HLA-A2 antigen was present more frequently in the recurrent otitis media group than in controls, indicating the existence of a relation between recurrent acute otitis and the HLA locus.
Hearing Loss
Nowhere has the development of molecular techniques had more consequence than with hearing loss, particularly hereditary deafness. About 50% of congenital diseases of the inner ear are genetically acquired. Genetic mapping relied mainly on kindred and linkage analyses until the recent increase in the number of available genetic markers (see Chapter 2). Research in otolaryngology directed at the molecular level continues at an accelerated pace. Future advances are certain to advance the understanding and management of maladies such as cancer. Somatic gene therapy, with targeted gene inactivation and insertional mutagenesis, ultimately may provide the means to alter disease.

PRINCIPLES OF PHARMACOLOGY AND MEDICAL THERAPY

2009-02-07T06:32:00.000-10:00

Although great strides have been made in surgical technology, some practitioners have overemphasized the role of regional surgical specialists. It is common during residency to focus on operative procedures, but on entering private practice, the fledgling otolaryngologist sometimes is surprised by the need to master previously neglected modes of medical therapy and by the infrequent summons to exercise surgical skills honed in residency. As the 1980s were marked by surgical advances, the 1990s emphasized recognition and medical management of disorders of the ear, nose, throat, head, and neck. Even greater progress is anticipated in the new millennium. This chapter offers general information and philosophical advice to enable clinicians to choose and administer pharmacotherapy effectively for conditions in which medical therapy is appropriate (Fig. 4.1).
DISEASES AND ASSOCIATED CONDITIONS
It is important to establish a specific diagnosis before treating. If therapy is to do more than relieve symptoms, the underlying cause of the problem must be identified and controlled specifically. An exact diagnosis is necessary because some pharmacotherapeutic agents are specific in action. For example, cromolyn is effective for managing immunoglobulin E–mediated allergic rhinitis but is ineffective in managing vasomotor rhinitis and polyp disease. An exact diagnosis also is important because the presence of unrecognized, complicating factors can diminish or negate the effectiveness of therapy. For example, nasal decongestant sprays can cause complicating rhinitis medicamentosa. A corollary to this rule is that if treatment must be administered without a specific diagnosis, the therapeutic response to the medication may render a clue to the proper diagnosis. Not all patients with infection need a culture and sensitivity study, but the response or lack thereof to the antibiotic empirically chosen is useful information for further treatment of the patient.
Establishing an accurate diagnosis on which to base treatment means there rarely is justification for “shotgun therapy,” that is, using enough drugs in the regimen to “hit everything.” An unfortunate example is the practice of some physicians who treat patients with nasal problems with an antibiotic for infection, an antihistamine for allergy, a decongestant for congestion, and a nasal steroid for nonspecific antiinflammatory effect. Such polypharmacy is expensive, is wasteful of medical resources, exposes patients to unneeded medications, to which allergies may develop or which may encourage bacterial resistance, and is entirely inappropriate.
The coexistence of medical conditions other than the one for which the patient is being treated affects the treatment chosen. Physicians must be aware of the medical status of patients and their current medications. For example, patients with diabetes mellitus may need more prolonged antibiotic therapy for an infection than may patients without diabetes. Patients with labile hypertension may respond to systemic decongestants with additional elevations of blood pressure. Patients taking tricyclic antidepressants or monoamine oxidase inhibitors may display a greater vasopressor response to such decongestants because of potentiation by these compounds.
DRUGS OF CHOICE
Dr. Hueston King first acquainted me with the adage, “To one who is good with a hammer, most things resemble a nail.” The proliferation of pharmacologic agents is difficult to follow, and physicians often develop a routine treatment of patients who have a certain set of signs and symptoms. New medications may have no benefit over existing ones, but wise practitioners should be familiar with the standard medications for managing common otolaryngeal disorders and be receptive to new agents as they are made available. This means that the physician’s armamentarium is constantly changing on the basis of reliable new information.
Characteristics and Actions of Drugs
A classic example of the difficulty in discerning the correct drug is in the choice of antibiotics. In no other form of pharmacotherapy has such a continuing explosion of available preparations occurred. By classifying drugs as members of a particular class, such as penicillins, macrolides, cephalosporins (first-, second-, third-, and fourth-generation), and quinolones, and becoming familiar with the general characteristics of the class, physicians can discern more easily the advantages and disadvantages of new preparations as they appear. Even more important is the problem of drug resistance and the mechanism by which this occurs for various antibiotics. This situation is constantly evolving. Physicians need to examine new data as they become available and must remain familiar with the incidence and patterns of antibiotic resistance in their particular geographic areas.
Cost-Benefit Considerations
Even in these days of managed care, with drugs often available to patients for only a nominal copayment, fiscal and social responsibility necessitates that physicians consider drug cost. On the other hand, the most expensive antibiotic is the one that does not work, and the physician’s experience and knowledge of community pathogen patterns of drug sensitivity can be helpful, as can the judicious use of cultures when previous therapy has failed. Table 4.1 lists the cost of antibiotics commonly used in otolaryngology.
The least expensive antibacterial agents are those that can be obtained as generic preparations, although unfortunately marked drug resistance can develop by the time these antibiotics become available in generic form. Parenteral antibiotics are much more expensive than those administered orally, and are rarely indicated in an outpatient setting. An obvious exception is the prescription of intravenous vancomycin for culture-proven methicillin-resistant staphylococci.
Responsible Antibiotic Selection
The increasing prevalence of antibiotic-resistant bacteria (Fig. 4.2, Fig. 4.3) is leading to new approaches in managing common respiratory infections in the outpatient setting (1). Failure of empiric therapy may necessitate culture of, for example, a specimen obtained from the middle meatus, to direct further antibiotic selection. Indiscriminate prescription of broad-spectrum antibiotics for trivial indications undoubtedly promotes the development of drug-resistant bacteria. Infectious disease experts recommend initial use of agents based on community experience and switching from broad- to narrow-spectrum drugs as soon as microbiologic confirmation allows (2).

The multiple factors involved in the choice of an antibacterial drug are summarized in Fig. 4.4. Further complicating decision making is the variety of mechanisms by which therapeutic effectiveness is assessed in vitro, such as area under the concentration-time curve and minimum inhibitory concentration (Fig. 4.5). To most physicians, these are unfamiliar terms, rarely mentioned during residency. Nevertheless, the practitioner must become familiar with these terms and apply them to particular antibiotics as they are introduced to decide whether the new drug offers any advantage over existing preparations. Physicians should avoid practices that hasten development of drug resistance, such as prescribing antibiotics for trivial indications, underdosing or administration for an inadequate length of time, and allowing periods of insufficient drug concentration.
ADMINISTRATION AND DURATION OF THERAPY
Administration and duration of therapy depend on the condition for which the patient is being treated. In general, parenteral therapy is used only if the manner of drug administration or the severity of illness makes oral therapy impractical or ineffective. For conditions such as otitis externa and rhinitis, some preparations are better administered topically than they are systemically. For example, corticosteroids administered intranasally rather than systemically are less likely to cause serious side effects, and the effect is concentrated in the desired area.
Duration of therapy varies with the condition for which the patient is being treated, but the usual tendency is to prescribe antibiotics for too short a period, often leading to recurrence or failure of full resolution of the infection. Many antibiotics now have specific time-length recommendations for specific diseases, such as acute sinusitis or chronic bronchitis. Other therapies administered for chronic disorders, such as steroid nasal sprays for chronic allergic rhinitis, must be monitored to prevent the patient from making them a lifelong habit with the attendant potential side effects and complications. In all instances, the physician must observe the patient and use response to therapy as a guide to duration of treatment.
SIDE EFFECTS AND INTERACTIONS
Information gained during drug development (Table 4.2) and contained in sources such as the Physician’s Desk Reference, USP Drug Information for the Health Care Professional, and package inserts alerts physicians about side effects and drug interactions. This information base grows as rapidly as the list of new drugs. For this reason, many physicians are turning to commercially available products, available in hard copy or computer format, that serve as guides to drug interactions and adverse effects. One such source is Drug Interactions, available from the U.S. Pharmacopoeia.
Numerous drug interactions have been determined. Failure to be aware of these interactions has severe consequences. Monoamine oxidase inhibitors and tricyclic antidepressants potentiate the effect of direct- and indirect-acting adrenergic agents. With monoamine oxidase inhibitors, this potentiation can be seen for as long as 14 days after the compounds are discontinued. Therefore, a-adrenergic agents should be used with caution and in lower doses than usual to treat patients taking either of these preparations. b-Blocking agents are commonly prescribed. Patients taking these preparations are more prone to anaphylactic reactions, as from medications, bee stings, and allergy immunotherapy, than the general population. The reactions often are refractory to conventional therapeutic measures such as injection of epinephrine.
An interaction often not appreciated is that of some antibiotics with oral contraceptives. Many drugs, including some macrolide antibiotics, tetracyclines, metronidazole, penicillins, and trimethoprim-sulfamethoxazole can decrease the effectiveness of oral contraceptives. The patient should be informed of her increased risk of pregnancy and advised to use other methods of contraception for at least one menstrual cycle beyond cessation of such antibiotic therapy (3).
Potentially life-threatening cardiac arrhythmias associated with prolongation of the QT interval have followed administration of the antihistamines terfenadine or astemizole with other drugs metabolized by the cytochrome P-450 enzyme system. Although both these drugs are now off the U.S. market, the fact that this interaction did not come to light for several years after the introduction of these preparations should signal caution to every physician. This problem emphasizes the importance of reporting adverse drug reactions when they occur. Reporting agencies such as the U.S. Pharmacopoeia monitor these reports and issue warnings when appropriate.
RISK OF TERATOGENIC EFFECTS
In prescribing for every female patient from menarche to menopause, it is prudent to ask about the last normal menstrual period to avoid prescribing a preparation that may harm an early pregnancy. As a practical matter, drug-induced fetal abnormalities are fairly rare. When they do occur, however, they represent a catastrophic event. In the general population, the incidence of serious major fetal malformation is 2% to 3%. This percentage encompasses defects incompatible with life, such as anencephaly, or those necessitating extensive surgical correction, such as cleft palate or cardiac defects. If the definition of malformation is broadened to include minor malformations, such as supernumerary digits, the rate approaches 7% to 10% of all births, drug exposure accounting for 2% to 3% of this group. Although the incidence of drug-related birth defects is low, we must strive to keep that percentage as close to zero as possible. As Neibyl (4) stated, “Humans are not rats.” Although almost all research involving the effects of drugs on a developing fetus is conducted with laboratory animals, the length of pregnancy and the time of development of various fetal parts differ radically between humans and rats. Nevertheless, the U.S. Food and Drug Administration has adopted labeling categories for drug use in pregnancy based on human and animal experience (Table 4.3). In general, pregnant patients should be treated with preparations that have the best record of safety. Consultation with the obstetrician may be necessary.
The so-called teratogenic period in human pregnancy spans the time from approximately 31 days after the last menstrual period through the tenth week after the last period. In other words, at about the time of the first missed period and for the next 6 weeks or more, drugs administered to a pregnant woman, who may not realize that her menstrual irregularity signals pregnancy, may affect vital areas of fetal development. The brain continues to develop until birth, and drugs given throughout pregnancy may affect it.
Antihistamines
Most antihistamines are not considered teratogenic. The best-controlled study with human subjects involved chlorpheniramine. This drug was shown not to increase the risk of birth defects in a series of more than 1,000 exposures in the first trimester. Triprolidine also was shown to be safe in a smaller series. A study involving 65 exposures to brompheniramine in the first trimester showed a threefold increase in the relative risk of birth defects associated with this common antihistamine, which is available by prescription and in over-the-counter preparations. Safety for use during pregnancy of the newer nonsedating antihistamines remains a subject of conjecture, although preliminary studies of administration of cetirizine and loratadine to animals are reassuring (5).
Decongestants
Epinephrine and phenylpropanolamine are associated with a substantial increase in risk of birth defects if administered during the first trimester, but pseudoephedrine has not shown any teratogenicity. Topical nasal decongestants are safer in that they have less severe systemic effects, but the risk of habituation and rebound rhinitis during pregnancy is higher than during the nonpregnant state.
Expectorants
Expectorant preparations containing iodides should be avoided because of the potential effect on fetal thyroid function, but guaifenesin is a safe and effective expectorant with no demonstrated teratogenicity. Some over-the-counter cough syrups contain large amounts of alcohol, as much as 25%. Repetitive consumption of these preparations, especially in amounts higher than the recommended doses, can have serious effects on both mother and fetus.
Analgesics
No clear answers have been obtained from the few studies of the use of analgesics during pregnancy. Aspirin is not recommended. It can reduce clotting capability, and its antiprostaglandin effect may decrease the effectiveness of uterine contractions. To a lesser extent, the same can be said of the numerous nonsteroidal antiinflammatory agents. Codeine has little teratogenic risk. In addition to the side effect of constipation, compounding a problem that often exists in pregnancy, there is risk of addiction.
Propoxyphene is probably the analgesic of choice for moderate to severe pain during pregnancy. In a prospective study, 686 first-trimester exposures to propoxyphene were associated with a 4.5% incidence of fetal malformation, a figure indicating that the teratogenic potential of propoxyphene is not great. Because the addiction risk of this drug has been established, including rare instances of neonatal withdrawal symptoms among infants of addicted mothers, propoxyphene should not be used for trivial indications.
Antibiotics
No teratogenicity has been demonstrated for the antibiotics commonly used in the management of otolaryngeal infections; however, some special factors deserve mention. During pregnancy, as a result of increased renal clearance and maternal blood volume, serum levels of amoxicillin and cephalosporins after administration are lower than those achieved in the nonpregnant state. Erythromycin apparently is not teratogenic. Its absorption and passage across the placenta are unpredictable. Except for reversible hepatic dysfunction associated with the estolate form, no serious undesirable side effects of the drug preclude its use in pregnancy.
Sulfonamides apparently have no deleterious effects on the fetus, but in the blood of neonates, they compete with bilirubin for binding sites on albumin, raising the level of free bilirubin in the serum and increasing the risk of kernicterus. Although long-acting sulfonamides and trimethoprim combined with sulfamethoxazole have caused congenital anomalies in animals, controlled trials with humans have not shown any teratogenic risk associated with these compounds. Tetracycline administered during pregnancy can retard skeletal growth and produce discoloration of the deciduous teeth. Clindamycin apparently presents no potential danger to the fetus.
CONCLUSION
Although the available modalities for medical management of problems encountered in otolaryngology are continually expanding and improving, the principles of application remain relatively constant. After the diagnosis is established, the drug most specific for the management of the disorder should be chosen. Factors such as cost-benefit ratio should be considered in the decision. The route and duration of administration must be individualized and altered according to the response obtained. The physician must be aware of side effects and the drug interactions possible because of the patient’s general medical status and other medications taken. Pharmacotherapy during pregnancy or to treat women who may become pregnant during therapy necessitates an even broader range of knowledge of the effects of the medication chosen.

MICROBIOLOGY, INFECTIONS, AND ANTIBIOTIC THERAPY

2009-02-07T06:30:00.000-10:00

This chapter is an overview of the antimicrobial agents most commonly used against the bacteria that cause infections of the ears, nose, throat, head, and neck. Because new bacterial resistance and new antibiotics appear regularly, this information should be supplemented with that in The Medical Letter on Drugs and Therapeutics, The Medical Letter Handbook of Antimicrobial Therapy, and the latest editions of The Sanford Guide to Antimicrobial Therapy, and the Pocket Guide to Antimicrobial Therapy in Otolaryngology–Head and Neck Surgery (1,2 and 3).
ANTIMICROBIAL AGENTS
Penicillins
Penicillins belong to the b-lactam family of antibiotics, so named because of the b-lactam molecular ring in their chemical composition. Because of the differing uses, it is instructive to consider them by categories.
Penicillins G and V are highly active against Streptococcus pyogenes (b-hemolytic group A), Streptococcus pneumoniae (most strains), actinomycosis, and a dwindling proportion of oral anaerobic organisms. They are inactivated by penicillinase produced by Staphylococcus aureus and other enzymes produced by a variety of gram-negative organisms, such as Haemophilus influenzae, Moraxella catarrhalis, and oral anaerobic organisms. These enzymes are collectively called b-lactamases, and they render many of the penicillin and cephalosporin agents inactive. Through a different mechanism, related to protein binding rather than enzymes, S. pneumoniae is becoming increasingly resistant to the penicillins and cephalosporins. Intermediate-level resistance may yet allow effective treatment with high doses of amoxicillin or second- and third-generation cephalosporins, but highly or multiply resistant strains are resistant to all penicillins, most cephalosporins, macrolides, tetracyclines, clindamycin, and chloramphenicol. Because gastric acid exerts an adverse effect on penicillins G and V, they are best administered on an empty stomach (1 hour before a meal).
Rashes occur among 5% of persons who take penicillin. They do not entirely preclude future use of penicillin because rashes recur among only 50% of these patients. When they are retreated with penicillin, these patients usually need little more than antihistamine treatment. Anaphylaxis is a different reaction, and it does not necessarily occur among patients with previous rash reactions. Because it is life threatening, anaphylaxis is considered a lifelong contraindication to future use of penicillin. All penicillins carry the same risk of causing anaphylaxis.
Antistaphylococcal penicillins resist penicillinase. Methicillin, oxacillin, cloxacillin, dicloxacillin, and nafcillin are agents in this category. Dicloxacillin attains the highest blood levels of any of the orally administered antistaphylococcal penicillins. Nafcillin is preferred for intravenous use, especially to treat patients with renal impairment, because it can be excreted through the liver. These agents are highly effective against Staph. aureus, even penicillin-resistant strains, except for a troublesome newcomer called methicillin-resistant staphylococcus, the prevalence of which reaches 10% of the staphylococcal strains in some hospitals. This organism is resistant to all penicillins and all cephalosporins. Except for methicillin, antistaphylococcal penicillins are active against streptococcal and most pneumococcal infections.
Aminopenicillins, such as ampicillin and amoxicillin, extend the activity spectrum to gram-negative organisms such as Proteus organisms, Escherichia coli, and H. influenzae, but Staph. aureus is resistant to drugs in this category. Furthermore, b-lactamase enzymes produced by 20% to 30% of H. influenzae strains and most strains of M. catarrhalis cause resistance to these agents. Aminopenicillins produce rashes more commonly than do other penicillins, especially if the patient has infectious mononucleosis (50% incidence of rash). Amoxicillin attains higher levels in the serum and middle ear fluid than does ampicillin, and it is well absorbed orally at meal times.
Augmented penicillins are those in which the penicillin is combined with an agent that inactivates resistance-producing b-lactamase enzymes. For the management of infection by staphylococci, H. influenzae, M. catarrhalis, anaerobic organisms, and others, amoxicillin is combined with potassium clavulanate (Augmentin, oral), and ampicillin is combined with sulbactam (Unasyn, parenteral). For the management of Pseudomonas aeruginosa infection and a broad spectrum of other infections, ticarcillin is combined with potassium clavulanate (Timentin, parenteral).
Antipseudomonal penicillins are active against most gram-negative bacteria but not gram-positive organisms, such as Staph. aureus. The activity of these agents against P. aeruginosa separates them from most other antibiotics. They are administered parenterally. Ticarcillin is more active than is carbenicillin. Piperacillin is the most active of all drugs in this category. In the management of serious pseudomonal infection, these drugs often are used in combination with an aminoglycoside, such as gentamicin, for a synergistic effect.
Cephalosporins
Cephalosporins also belong to the b-lactam family of drugs. This chemical relation probably means that patients with a history of penicillin anaphylaxis should avoid cephalosporins; however, cephalosporins are commonly and safely used by patients with a history of penicillin rashes. These drugs are categorized into first, second, and third generations. In general, first-generation agents are most active against gram-positive bacteria, and third-generation agents are highly active against gram-negative bacteria. Second-generation agents occupy an intermediate position. It is easiest to be familiar with one oral agent and one or two parenteral agents in each generation. For information about other agents, see the Pocket Guide to Antimicrobial Therapy (2).
First-generation oral cephalexin (Keflex) is highly effective against gram-positive organisms such as streptococci, pneumococci except for penicillin-resistant strains, and staphylococci except the methicillin-resistant strains. It is also active against a few gram-negative bacteria, but Staph. aureus is the organism against which it is most commonly used. For parenteral use, cefazolin (Ancef, Kefzol) produces the longest duration of action of the first-generation agents. Its antistaphylococcal activity is widely used in prophylaxis against surgical infections after operations in which a skin incision is made.
Second-generation cefuroxime is available for both parenteral (Zinacef) and oral (Ceftin) use. Both are highly active against gram-positive cocci, but more important, they are effective against H. influenzae and M. catarrhalis, including the ampicillin-resistant strains. Pneumococci resistant to penicillin (intermediate level) can be controlled with cefuroxime or similar agents, such as cefprozil (Cefzil) or cefpodoxime (Vantin), but these agents are ineffective against high-level resistant pneumococci. Cefpodoxime and loracarbef (Lorabid) are so similar to cefuroxime in activity and use that for simplicity they can be considered second-generation equivalents. As oral preparations, these agents are useful in managing acute sinusitis and otitis media. For intracranial complications of acute sinusitis or otitis media, cefuroxime penetrates the blood-brain barrier fairly well.
Third-generation cephalosporins include three of special importance in the management of infections of the ear, nose, throat, head, or neck. Cefixime (Suprax) is an oral agent highly active against H. influenzae and M. catarrhalis, even the ampicillin-resistant strains. Acute sinusitis and otitis media caused by these organisms can be managed effectively with once-daily dosing in a tablet or suspension preparation. If treatment fails, the infection probably is pneumococcal, against which this third-generation agent is less effective than are the first- and second-generation agents. Ceftibutn (Cedax) is roughly equivalent to cefixime.
Ceftriaxone (Rocephin) is a parenteral agent effective against H. influenzae, M. catarrhalis, S. pneumoniae, including most penicillin-resistant strains, Neisseria meningitidis, and Neisseria gonorrhoeae. Because it penetrates into the cerebrospinal fluid and because it has a broad spectrum of activity against organisms that cause upper respiratory infections, ceftriaxone usually is the first choice for treating patients with intracranial and orbital complications of acute sinusitis and otitis media. It is also the first choice for treating patients with oral gonococcal infections. Ceftriaxone has been found useful for single-dose injection therapy for acute and subacute otitis media. In many respects, cefotaxime (Claforan) is an equivalent agent. Ceftazidime (Fortaz) is a parenteral agent highly active against P. aeruginosa. It is also active against other gram-negative bacteria, including H. influenzae and N. gonorrhoeae, and it penetrates well into the cerebrospinal fluid. In general, third-generation cephalosporins are less active against gram-positive bacteria, such as Staph. aureus, than are their first-generation counterparts. Anaerobic bacteria, such as Bacteroides fragilis, also are relatively resistant.
Other b-Lactam Antibiotics
Imipenem (combined with cilastatin in Primaxin) and meropenem (Merrem) are parenteral agents that exert a broad spectrum of antimicrobial activity. They are active against S. pyogenes, most S. pneumoniae organisms, Staph. aureus (except methicillin-resistant strains), H. influenzae, B. fragilis and most anaerobic organisms, and the coliforms, including P. aeruginosa. Because of its broad spectrum, imipenem or meropenem can be used as a single agent against infection by unidentified organisms, but cerebrospinal fluid penetration is not assured. Because resistance can appear during therapy for pseudomonal infections, a b-lactam agent should not be used as a single agent. Patients with penicillin allergies may be allergic to imipenem. Aztreonam (Azactam) is a parenteral agent active against aerobic gram-negative organisms such as P. aeruginosa. Its distinguishing feature is its safety in the treatment of patients with penicillin allergies.
Macrolides
Erythromycins are effective therapy for respiratory infections due to streptococci, most pneumococci, mycoplasmata, and chlamydiae, legionellosis, diphtheria, and pertussis. Most Staph. aureus infections are susceptible to erythromycins, but resistance can develop during therapy. Management of H. influenzae infection with erythromycins is effective if a sulfonamide is added to the regimen (the combination Pediazole). Pneumococci resistant to penicillin are likely resistant to macrolides as well.
Preparations have been devised to minimize the degree of nausea and vomiting that accompanies use of erythromycin. The ethylsuccinate preparation can be taken with meals. Others need enteric coatings. Newer macrolides such as azithromycin (Zithromax) and clarithromycin (Biaxin) are more tolerable in terms of gastrointestinal effects. More important, they extend their antimicrobial activity to include H. influenzae and M. catarrhalis. Erythromycins and clarithromycin elevate theophylline levels with stimulating side effects if the drugs are taken concomitantly.
Clindamycin
Clindamycin (Cleocin, oral or parenteral) is highly active against gram-positive cocci, including many but not all strains of penicillin-resistant pneumococci. Clindamycin is especially effective in the management of Staph. aureus infection, including infection with many methicillin-resistant strains. It is also highly effective against anaerobic infections of the aerodigestive tract, particularly with B. fragilis, which causes infection deep in the neck and draining ears and causes septic shock. Osteomyelitis is successfully managed with clindamycin because the organism is concentrated in bone. The combination of clindamycin and gentamicin is effective prophylaxis against all the common contaminants of surgical wounds, such as Staph. aureus, P. aeruginosa, and anaerobic organisms.
Nausea or diarrhea is sometimes intolerable after oral administration. Pseudomembranous colitis due to overgrowth of enteric Clostridium difficile is a serious complication attributed to clindamycin, but it also can complicate therapy with many other broad-spectrum agents. Treatment requires oral metronidazole or vancomycin. Patients who need clindamycin may be pretreated for several days with metronidazole to prevent colitis.
Tetracyclines
Tetracyclines are effective against Mycoplasma, Chlamydia, and Legionella infections. Most streptococcal, staphylococcal, and H. influenzae infections are resistant to tetracyclines, which means these drugs should be recommended only after culture studies show susceptibility of the infecting organisms. Because tetracyclines stain enamel in forming teeth, use of these agents is avoided in the care of children younger than 10 years and of women who may be pregnant. Tetracyclines predispose users to sunburn. Milk products and antacids (calcium, magnesium) interfere with absorption.
Chloramphenicol
Chloramphenicol (Chloromycetin, oral and intravenous) exerts broad-spectrum activity against gram-positive cocci, including most penicillin-resistant Staph. aureus, and most gram-negative bacteria, including H. influenzae and the anaerobic organisms of the aerodigestive tract. Pseudomonas organisms, however, are resistant, as are penicillin-resistant strains of pneumococci. Chloramphenicol penetrates readily into the cerebrospinal fluid. Fatal bone marrow depression occurs among 1 of 24,000 patients who take chloramphenicol. This limits its use to management of life-threatening infection when other effective agents are unavailable, as in intracranial extension of sinusitis or otitis media in a patient with a history of anaphylactic reaction to b-lactam agents, such as penicillin.
Quinolones, Fluoroquinolones
The quinolone-fluoroquinolone group of antibiotics has a broad spectrum of effectiveness. They are useful in the management of infections that are resistant to several drugs. They have the additional advantage of being structurally unrelated to other classes of antibiotics, so they may be used to treat patients who are allergic to penicillins, sulfonamides, erythromycin, or cephalosporins.
Ciprofloxacin (Cipro) and ofloxacin (Floxin) are called antipseudomonas quinolones. They are important because of their effectiveness in controlling P. aeruginosa infection when given orally. Ciprofloxacin has greater therapeutic potency and causes fewer adverse side effects than does ofloxacin. Both agents elevate theophylline levels if such drugs are taken concomitantly. Ciprofloxacin has been effective in the treatment of patients with cystic fibrosis who have bronchitis, of those with pseudomonal sinusitis, and of those with malignant necrotizing otitis externa.
Levofloxacin (Levaquin), trovafloxacin (Trovan), gatifloxacin (Tequin), moxifloxacin (Avelox), and gemifloxacin (Factive) are classified as respiratory quinolones and are useful in the management of respiratory and pharyngeal infections. They are effective against b-hemolytic S. pyogenes, S. pneumoniae, including penicillin-resistant strains, and Staph. aureus, including methicillin-resistant strains. They also are active against H. influenzae and M. catarrhalis, including b-lactamase-producing strains, and against atypical pathogens such as Mycoplasma, Chlamydia, Legionella, and Bordetella pertussis organisms. They have the advantage of being long acting, so once-a-day dosing is effective. They are best absorbed if taken 1 hour before milk, antacids, or vitamin preparations that contain minerals.
Gatifloxacin, moxifloxacin, and trovafloxacin are the more potent antibiotics in this group. They are also active against anaerobic organisms such as Bacteroides and Peptostreptococcus. Because of reported adverse reactions, including liver damage, trovafloxacin preparations have been removed from the market. Intravenous trovafloxacin is used primarily in cases of severe or life-threatening infections, such as meningitis, when there are no other good options.
Vancomycin
Vancomycin (Vancocin, parenteral) is highly active against gram-positive cocci, including methicillin-resistant strains of Staph. aureus, penicillin-resistant strains of pneumococci, enterococci, and gonococci. Because it is unrelated to any other class of antibiotics, vancomycin is useful in the treatment of patients with penicillin allergies. High concentrations in the serum of patients with renal impairment can cause ototoxicity. Vancomycin does not cross the blood-brain barrier effectively, so when resistant pneumococcal infections extend intracranially, vancomycin therapy should be combined with ceftriaxone or trovafloxacin. Because vancomycin may be the last remaining agent still effective against highly resistant strains of staphylococci, pneumococci, and enterococci, this drug should be reserved for such serious infections and not used against bacteria that can be effectively controlled with other antimicrobial agents.
Metronidazole
Metronidazole (Flagyl, oral or parenteral) is highly active against anaerobic bacteria, including B. fragilis. It is useful in management of oral infections. All aerobic bacteria are resistant to this agent, but combination therapy (metronidazole plus any of the penicillins, cephalosporins, or quinolones) can be recommended to manage deep neck abscesses, chronic sinusitis, draining cholesteatoma, and intracranial extension of these infections. Metronidazole penetrates the blood-brain barrier well. Against antibiotic-induced pseudomembranous enterocolitis, metronidazole is much less expensive than vancomycin and is the preferred choice. Alcohol should not be consumed by patients taking metronidazole lest a reaction such as that to disulfiram (Antabuse) occurs.
Aminoglycosides
Systemic aminoglycosides are administered by the parenteral route only. Gentamicin, tobramycin, and amikacin are used against P. aeruginosa and other hospital-acquired infections, such as Serratia infection. Gentamicin (generic) is inexpensive and usually is used as the first-choice agent in this category unless resistance is expected and the infection is progressing rapidly. Resistance to gentamicin does not necessarily imply resistance to tobramycin and amikacin, which are used as alternatives. For serious pseudomonal infection, treatment is improved if aminoglycosides are combined with antipseudomonal penicillins, such as tobramycin plus ticarcillin. These combinations produce a synergistic effect that reduces resistance or retards its emergence.
Anaerobic infections are almost universally resistant to aminoglycosides, as are 10% or more of Staph. aureus infections. A combination of gentamicin with clindamycin eliminates this problem. This combination is highly effective in the management of head and neck wounds with mixed infections and deep neck infections, and it provides excellent prophylaxis against surgical wound infections.
Ototoxicity of these agents places constraints on parenteral use, particularly of streptomycin, kanamycin, and neomycin. The incidence of aminoglycoside ototoxicity for gentamicin, tobramycin, and amikacin is commonly stated as approximately 10%, but it is worse among patients with impaired renal function, which allows toxic serum levels to accumulate. Careful monitoring indicates the dosages needed to avoid ototoxicity (2).
Rifampin
Rifampin is an important oral agent for managing the nasopharyngeal carrier state of H. influenzae and meningococcus. In combination with other antistaphylococcal drugs, such as ciprofloxacin, it controls resistant Staph. aureus and resistant pneumococci. It is sometimes combined with clindamycin or a second-generation cephalosporin. Mupirocin (Bactroban) ointment plus oral rifampin is useful in the management of chronic staphylococcal infection of the nostrils.
Sulfonamides
Sulfonamides are older agents effective in the management of H. influenzae infection but not of pneumococcal, streptococcal, and staphylococcal infections; however, sulfonamides may be used in combination with penicillin, cephalexin, macrolides (erythromycins), or even clindamycin to broaden the antimicrobial spectrum of coverage of these agents. Sulfonamides commonly cause rashes and photosensitivity (sunburn). Sulfamethoxazole plus trimethoprim (Bactrim, Septra) in combination is more potent than either agent alone.
TREATMENT STRATEGIES
The physician’s choice of antimicrobial agent is influenced by the following factors: (a) probable infecting organism, site of infection, and community prevalence, (b) probability of resistance to agent, (c) patient intolerance or allergy to agent, and (d) cost of agent. For example, amoxicillin may be an inexpensive first choice to manage acute otitis media, but it is not for the approximately 10% of patients with infections by organisms resistant to the drug. For physicians or patients who would be highly dissatisfied with the possibility of a treatment failure, one of the more expensive alternatives may be a better first choice. Physician and patient preferences and special situations may take precedence over the general recommendations listed in Table 5.1. Most well-established acute infections necessitate 10 days of therapy. Treatment begun very soon after the onset of infection may be of shorter duration. Chronic infection may necessitate several weeks or months of treatment and may not clear without surgical drainage.
Otitis Media
Acute otitis media is caused by S. pneumoniae, H. influenzae, or M. catarrhalis, also known as Branhamella catarrhalis. Amoxicillin controls most strains of S. pneumoniae, but more than 20% of strains of H. influenzae are resistant, as are more than 80% of strains of M. catarrhalis. Erythromycin plus sulfonamide is slightly more expensive than amoxicillin, but it is more likely to clear the infection because it covers all the pathogens except penicillin-resistant pneumococci. Amoxicillin with clavulanate also is used to control the common pathogens, as are cefuroxime, cefprozil, and cefpodoxime. Cefixime can be administered once a day in a pleasant-tasting suspension for management of H. influenzae and M. catarrhalis infection, but failures are probable caused by pneumococcal resistance. Ceftibuten is similar to cefixime.
Penicillin-resistant pneumococci are prevalent pathogens among children who have received prolonged low-dose antimicrobial prophylaxis and those exposed to other children in large day-care centers. They pose special treatment problems. In a study conducted in New York City, investigators found pneumococcus in 26% (31 of 115) of middle ear aspirates from children with otitis media (4). Nonsusceptible strains were identified in 16% of the pneumococcal infections, and only cefuroxime had consistent activity against the moderately resistant strains. Another set of investigators (5) emphasized the growing prevalence of penicillin-resistant S. pneumoniae and its association with the use of two or more antibiotics to manage pediatric upper respiratory tract infections. The authors emphasized the need for continuing education of primary care physicians.
Intermediate-level resistance usually responds to amoxicillin with or without clavulanate, especially if dosages are high. An alternative is to administer ceftriaxone by means of injection. High-level resistance necessitates vancomycin therapy or possibly a quinolone frequently used to manage respiratory tract infection—levofloxacin, gatifloxacin, moxifloxacin, or gemifloxacin. Chronic otitis media with effusion is caused by the same pathogens as acute otitis media and is managed with the same antimicrobial agents.
Sinusitis
Acute sinusitis is caused by the same bacteria as acute otitis media. Drug choices are the same; however, if sinusitis extends intracranially, pneumococcal infection is suspected, and agents must be selected that penetrate the blood-brain barrier, such as ceftriaxone, cefuroxime, or trovafloxacin. Orbital extension implies impending central nervous system extension, and it is similarly managed. Chronic sinusitis is caused by a mixture of various anaerobes that frequently includes Staph. aureus. Clindamycin or amoxicillin-clavulanate is a rational choice. Various fungi and Pseudomonas organisms in extensive polyposis also may be causative. Itraconazole (Sporanox) controls fungi. Ciprofloxacin controls Pseudomonas infection.
Pharyngitis
Pharyngitis is caused by S. pyogenes among 30% of persons with sore throats during the winter months as ascertained with throat culture studies; however, N. gonorrhoeae, Mycoplasma, Chlamydia, and Haemophilus organisms are other important causes of sore throat that can be controlled with antimicrobial therapy. Other likely agents are the anaerobic organisms involved in tonsillitis. Diphtheria is rare. All of these organisms produce negative “strep” cultures of the throat, which illustrates the folly of routinely withholding antibiotic therapy until strep culture results prove positive. Clinical judgment is required. Factors that favor bacterial infection and the need for antibiotic treatment include (a) a history of bacterial infection in the household, (b) prolonged or severe sore throat, (c) severe erythema, exudate, or lymphadenopathy, (d) absence of hoarseness, which indicates viral laryngitis.
Tonsillitis
Tonsilloadenoiditis is most frequently caused by S. pyogenes, but a variety of anaerobic organisms often are present in a mixed infection. These commonly produce b-lactamase enzymes that render penicillin ineffective even against the streptococci. Therefore, clindamycin often is more effective. Augmented amoxicillin also is effective, but if mononucleosis is the principal infection, amoxicillin has a 50% probability of producing a severe rash. Clindamycin, cephalexin, or penicillin plus metronidazole can avoid that problem. Extensive exudate on the tonsils suggests mononucleosis among adolescents and children. Antibiotic therapy may not control Epstein-Barr virus, but it does control secondary bacterial invaders.
Laryngitis
Acute laryngitis usually is a viral infection that resolves with a few days of voice rest. Prolonged hoarseness suggests a secondary bacterial infection to be controlled with erythromycin or another macrolide plus sulfonamide or a quinolone commonly used to manage respiratory tract infection.
Epiglottitis
Epiglottitis is most frequently caused by H. influenzae. Parenterally administered sulbactam-ampicillin, cefuroxime, or ceftriaxone is a rational choice. Trovafloxacin administered intravenously can be used to treat patients with a history of penicillin anaphylaxis. Airway management takes priority.
Croup
Croup (subglottic) usually is a viral infection, but 10% of patients have secondary infections with Staph. aureus or H. influenzae. If thick yellow secretions are encountered, administer the same agents as used for epiglottitis.
Wounds
Deep neck abscesses and wounds subjected to mucosal infection or chronic intracranial infection of ear or sinus origins are caused by mixed bacterial flora with anaerobic organisms predominating. Clindamycin covers Staph. aureus, all cocci, and anaerobic organisms, but when pseudomonal infection is suspected, gentamicin should be added. Neither of these agents, however, reliably penetrates into central nervous system tissues, for which nafcillin plus metronidazole is needed. If Haemophilus or pseudomonal infection is anticipated, ceftazidime can be administered. Trovafloxacin administered intravenously and vancomycin are contingency drugs for patients with a history of penicillin anaphylaxis.
Mastoiditis
Management of acute mastoiditis with subperiosteal abscess requires coverage of the same microbial possibilities as acute otitis media. Pneumococci and H. influenzae tend to intracranial extension. Ceftriaxone is the initial choice. Chronic suppurative otomastoiditis, including cholesteatoma, adds Staph. aureus, Proteus organisms, B. fragilis, and other anaerobic organisms to the infectious polymicrobial mix. Smelly pus suggests the presence of anaerobic bacteria. Pseudomonas also is a frequent contaminant. Intracranial extension necessitates use of combinations that penetrate the central nervous system, such as ceftazidime plus augmented ampicillin or ceftazidime plus metronidazole plus nafcillin.
Suppurative Otitis
Ototopical therapy is only as effective as the cleanings the physician provides, because infection advances in the opposite direction as the drainage flows. The draining ear of acute otitis externa or suppurative otitis media necessitates combination drug therapy—polymyxin for the pseudomonal infection and neomycin for the Staph. aureus, Proteus organisms, and others. Either of these agents alone is likely to produce treatment failure; Cortisporin or Coly-Mycin S includes both. Some Pseudomonas organisms are resistant to polymyxin, but gentamicin drops can be added to or alternated with the Neosporin-polymyxin preparation. Quinolone otic drops such as ciprofloxacin and ofloxacin are highly effective, and they are particularly indicated in the treatment of patients with a tympanic membrane that is not intact. In a study involving 381 patients with chronic suppurative otitis media, investigators found that Pseudomonas organisms (27%) and Staph. aureus (24%) were the important organisms isolated. Topical aural preparations of ciprofloxacin and gentamicin were the most effective agents (6).
Otomycosis due to Aspergillus infection usually is managed with acidifying ear drops that contain acetic or boric acid, such as Acetasol and Domeboro. Other antiseptics, such as Merthiolate, gentian violet, and iodine, sometimes are used. Topical antifungal agents, such as clotrimazole (Lotrimin) work for candidiasis. Tom (7) reported that according to results of studies of animals, clotrimazole, miconazole, and tolnaftate appear to be safe in terms of ototoxicity, but entian violet can cause severe damage. The residue left by the nystatin preparation is cause for concern and a reminder that both the active ingredient and the vehicle must be considered in terms of safety.
Prophylaxis
If cellular tissue levels of properly selective antibiotics are high at the moment of contamination, such as incision, surgical wound infections and sepsis are remarkably reduced. Prophylaxis for surgical wound infections requires administration of the initial dose an hour or so before incision time and continuation for 24 hours or until the period of wound contamination, such as suture line leakage, has passed. For incisions through the skin, staphylococcal infection must be addressed, and cefazolin is the most commonly used agent. Incisions through mucous membranes, especially pharyngeal membranes, can cause contamination by anaerobic organisms. Wound breakdown among hospitalized patients carries risk of pseudomonal infection. Gentamicin plus clindamycin covers all these contingencies. This prophylaxis yields excellent results in head and neck tumor surgery. Postoperative infection associated in uninfected nasal or otologic operations are so uncommon that statistical proof of the efficacy of prophylaxis is unlikely. If prophylaxis is justified, it is by inference from its effectiveness in surgical procedures in general. If the risk of a serious or poor outcome outweighs the risk or cost of administration of antibiotics, treatment may be advisable.

DIAGNOSTIC IMAGING

2009-02-07T06:29:00.000-10:00

This chapter provides an overview of diagnostic imaging in otolaryngology and head and neck surgery. It presents the principles and current modalities used in regional evaluation of the head and neck. The indications, applications, and limitations of conventional screening methods and high-technology imaging are delineated for a variety of otolaryngologic disorders.
PRINCIPLES OF IMAGING
A diagnostic imaging study is the most common consultation that otolaryngologists and head and neck surgeons request for a patient. Because many of the supporting and deep structures of the head and neck are beyond direct topographic evaluation, even with fiberoptic endoscopes and telescopes, further anatomic and physiologic information must be obtained for the temporal bone, skull base, paranasal sinuses, soft tissues of the neck, larynx, and other structures by means of diagnostic imaging. This does not mean that every patient needs an imaging study. Some patients need only a sensitive and thoughtful examiner. Other patients need conventional plain radiographs to complete the assessment. Others, however, need high-technology imaging for an accurate diagnosis and optimal treatment planning.
The influence of professional development and the team approach to diagnostic imaging is growing. Neuroradiologists have long gravitated to the field of head and neck radiology, and interventional specialization has extended far beyond this discipline. Angiography provides a model in which diagnostic imaging has led to interventional imaging and the training of dedicated specialists. A radiologic examination must be treated as a consultation to derive optimal information for formulating the best working diagnosis. This is the essence of effective diagnostic imaging, and it is achieved through effective communication between otolaryngologist and radiologist and through mutual analysis of the clinical problem and radiologic evidence. Consultation involves a well-prepared requisition, a telephone call, or a copy of the referring letter or consultation report.
The consulting team members must establish the optimal working diagnosis. Treatments may vary, but there is only one diagnosis, and it must be qualitatively and quantitatively effective (Table 6.1). Qualitative aspects of diagnosis usually lie within the field of the pathologist. However, the diagnostic image can provide qualitative answers to questions about whether disease exists, whether there is a specific disease process, such as a fracture, or whether a group disorder, such as bone destruction or cyst formation, can be identified. Diagnostic images also contain answers to quantitative questions about the extent of disease in all three dimensions, about disease that crosses regional boundaries that affect management, and about whether the disease is a local manifestation, metastatic condition, or systemic disorder. Imaging can help to inform the clinician about the presence and nature of a specific anatomic or physiologic derangement.
The foregoing are the types of issues clinicians formulate for imagers and for which solutions can be provided. However, routine questions receive only routine responses. Fifty percent of diagnostic information can be lost from computed tomography (CT) and magnetic resonance imaging (MRI) if the studies are not tailored to provide specific answers to pathologic anatomic and physiologic questions.
IMAGING MODALITIES
Conventional Imaging
The modalities representative of conventional imaging are listed in Table 6.2. Regional plain-film routines, series, or examinations are used to survey the temporal bone (Table 6.3) and to examine the paranasal sinuses (Table 6.4). A variety of radiographic signs can be recognized from alterations in the interfaces and contrasts among bone, soft tissue, and air in accordance with the 16 shades of gray recognized by the human eye. The radiographic signs of paranasal sinus disease are listed in Table 6.5.
Familiarity with conventional radiographic signs and a protocol for careful examination of radiographs based on proper clinical information leads to effective interpretation. The conventional temporal bone examination rarely is used today. Computed tomographic examinations are readily available and provide superior temporal bone information.
Acquisition of conventional x-ray films of the sinuses is the most common radiographic examination performed in the practice of otolaryngology. More than half of all conventional radiographic studies requested are of the paranasal sinuses, and these may be augmented by other radiographs, such as those obtained in the right and left orbital oblique projections and those of the nasal bones and zygomatic arches. Selective views, such as a lateral radiograph of the nasopharynx for measuring the adenoids or of the larynx and trachea for detecting a foreign body, are also commonly requested. These regional screening examinations and selective views should be reviewed to assure technical quality before the patient leaves the radiology department.
Some of the conventional imaging modalities listed in Table 6.2 rarely are requested because newer forms of imaging have more to offer. However, panoramic tomography of the teeth, mandible, and maxilla and a barium swallow examination of the hypopharynx and esophagus frequently are requested. Modified barium swallow is an actively monitored examination in which the radiologist’s attention must be focused on clear identification of the clinical problem to be solved.
High-technology Imaging
High-technology imaging (Table 6.6) includes CT, MRI, angiography, diagnostic ultrasonography, radionuclide scanning, and positron emission tomography. High-technology imaging supplements the screening information obtained with conventional radiographic examinations. The expansion of information occurs structurally. For example, CT expands the gray scale of conventional radiography into the thousands. Expansion also occurs physiologically, as in low-resolution radionuclide scans. Magnetic resonance imaging and angiography provide anatomic and physiologic information. High-technology imaging allows intervention such as ultrasound-guided fine-needle aspiration (FNA) biopsy or intra-arterial embolization.
HEAD AND NECK RADIOLOGY BY REGION
Temporal Bone
The temporal bone is the most complex anatomic structure in the body, and pathologic changes may induce only modest radiologic signs. The proximity of the temporal bone to important bony structures, such as the base, vault, and foramina of the skull, leads to summation and superimposition, which cause masking effects of fine details on conventional images. Radiologic investigation of the temporal bone complex and related structures may be inadequate unless high-technology imaging modalities are used (Table 6.6). Before sophisticated imaging modalities were developed, standard projections (Table 6.3), pneumoencephalography, contrast cisternography, and, beginning in the 1950s, complex motion or pluridirectional polytomography were widely used for the evaluation of temporal bone disease.
Conventional temporal bone projections still are used in many parts of the world where CT and MRI are not readily available. Conventional modalities depict the key attic, aditus, and antral region, mastoid pneumatization, and petrosa. Some pathologic conditions, such as chronic suppurative otitis media with or without cholesteatoma, acute coalescent mastoiditis, and large tumors of the internal auditory canal or the cerebellopontine angle such as acoustic neuroma, meningioma, and subarachnoid cyst, can be identified primarily from evidence of bone destruction. Pneumoencephalography and cisternography were used mainly to depict acoustic neuroma by using contrast medium to accentuate filling defects. Complex motion tomography supplemented these interventional procedures. These techniques allowed multiplanar assessment of bone destruction. However, acoustic neuroma was identified from bone destruction in only 60% of instances. A tumor had to reach a large size to produce enough bone destruction to be radiologically recognized. Complex motion tomography allowed assessment of congenital malformations, otosclerosis, and temporal bone fractures.
Computed tomography can be performed with high-resolution bone algorithms, and a series of contiguous or overlapping CT sections can be processed to generate excellent images. Spatial resolution in MRI has increased such that information offered about the cerebellopontine angle, internal auditory canal, cochlea, and vestibule exceeds that obtained with CT. A contrast-enhanced study is of value in many situations. Magnetic resonance imaging and CT are not mutually exclusive examinations and are frequently combined to fully assess lesions of the base of the skull. Angiography is reserved for the detection of arterial stenotic lesions and arteriovenous fistulae, for the evaluation of tumor vascularity, and for preoperative embolization.
Computed tomography and MRI have become the radiologic methods of choice for most disorders of the ear and temporal bone. These high-technology studies also can be used to evaluate the neighboring skull base and related structures of the middle and posterior cranial fossae. Magnetic resonance imaging and CT are complementary. Computed tomography is good for imaging diseases that affect cortical bone, air spaces, and some soft tissue lesions of the temporal bone. Magnetic resonance imaging is excellent for evaluating soft tissues, cerebrospinal fluid, and blood vessels. However, the thin cortical bone and air-containing spaces of the middle ear and mastoid cause signal voids, which make it difficult to differentiate air from bony septations. Therefore, high-resolution CT is still the procedure of choice for bone assessment. Computed tomography is excellent for evaluating congenital anomalies, including cochlear and labyrinthine anomalies, with a special emphasis on Mondini dysplasia, congenital microtia, and other middle ear abnormalities. The degree of otomastoid pneumatization, the status of the ossicular chain, the course and position of the facial nerve, the positions of the internal carotid canal, sigmoid sinus, and jugular bulb, the thickness of the atretic plate, and the dimensions of the middle ear all are important in assessing operability. In most cases, intravenous administration of contrast material is not needed unless the study is performed to evaluate the central nervous system or vascular structures. The main disadvantages of CT are that it cannot be used to image the internal auditory canal and that it has limited value in imaging in multiple planes because many patients cannot be positioned for direct coronal or sagittal images.
In the diagnosis of erosive disease of bone, such as chronic otitis media with cholesteatoma, CT with bone window settings provides the best information. The locations, extent, and nature of the complications of cholesteatoma are ideally evaluated with CT. Acute coalescent mastoiditis, which usually occurs as masked mastoiditis, can be identified by means of thin-section axial and coronal CT examinations. Intracranial complications, such as sigmoid sinus thrombosis, extradural and subdural abscesses, and brain abscess, are best detected with contrast-enhanced CT with both bone and soft-tissue window settings. Even with MRI, dural sinus thrombosis is a difficult imaging diagnosis. Magnetic resonance angiography and MR venography are state-of-the-art examinations for evaluation of this dangerous clinical condition. Computed tomography allows the relative identification and differentiation of soft-tissue abnormalities associated with chronic ear disease, such as granulation tissue, mucopurulent effusions, cholesteatoma, and cholesterol granuloma. High-resolution CT is an excellent and sensitive means of imaging temporal bone fracture lines. Magnetic resonance imaging is recommended if the presence of coexisting intracranial abnormalities is suspected. Hemotympanum, ossicular chain disruption, and injury to the facial nerve canal are common radiologic findings. Posttraumatic cerebrospinal fluid leak is still best depicted on intrathecally enhanced CT scans.
Computed tomography with intravenous administration of contrast medium has been used routinely in screening for masses in the cerebellopontine angle. Acoustic neuroma is the most frequent tumors in this location. Computed tomography can accurately depict lesions larger than 1 cm in diameter, but it is generally unreliable for smaller tumors. Since the introduction of paramagnetic contrast agents, the usefulness of MRI has greatly improved. When a retrocochlear lesion is suspected on clinical grounds, MRI with gadolinium enhancement is the imaging modality of choice (1). It is superior to CT for evaluating acoustic neuroma because with contrast medium it can depict tumors smaller than 0.8 cm in diameter. Magnetic resonance imaging with gadolinium–diethylenetriamine pentaacetic acid contrast enhancement can help in the assessment of primary soft-tissue abnormalities in the temporal area, such as facial nerve lesions, labyrinthine schwannoma, and vestibular neuronitis. The superiority of MRI also is recognized in the evaluation of other lesions that affect the cranial nerves and cerebrospinal axis (2).
Other diagnostic modalities for vascular imaging of the temporal bone area include superselective angiography and digital subtraction angiography for screening. Angiography also can be used to direct interventional procedures. These modalities are useful in evaluating primary vascular tumors, such as glomus jugulare tumor and its extension beyond the jugular foramen into the skull base and temporal bone. These studies also are important in recognizing anomalies that can lead to surgical disasters. An aberrant middle ear internal carotid artery or high jugular bulb can be identified by means of primary vascular screening studies, by means of reconstructive or direct CT, and by means of MR angiography.
Combination radionuclide bone and gallium scans are essential in diagnosing malignant external otitis (osteomyelitis of the temporal bone) and in assessing stage and response to treatment. These scans provide physiologic information beyond the morphologic findings on CT scans.
Paranasal Sinuses
The paranasal sinuses are air-filled cavities surrounded by bone. They are inaccessible to direct clinical examination unless telescopic intervention is used. Cooperation between clinician and imager is essential for effective treatment decisions and follow-up evaluation, especially for endoscopic techniques, in which the osteomeatal complex must be thoroughly studied with CT.
Conventional plain radiography once was the imaging modality of choice in the evaluation of the paranasal sinuses. The clinical and radiographic emphasis was on disease in the maxillary and frontal sinuses. Superimposition of structures precluded accurate evaluation of the anatomic relations of the ethmoid sinuses and osteomeatal complexes. With the recognition of the importance of the osteomeatal complex in sinus disease and a change in therapeutic approach, CT has replaced conventional radiography as the primary diagnostic modality.
The target structures and views for conventional plain radiographic examination of the paranasal sinuses are summarized in Table 6.4. A complete series of sinus radiographs usually includes Waters, Caldwell, lateral, and submentovertex views; right and left oblique orbital views are obtained if the orbital apex or optic canal approximates the area of concern. Additional views may be needed to study the nasal bones or zygomatic arches. Panoramic tomography or focused dental radiographs can be used to evaluate apical dental disease that affects the maxillary sinuses. Conventional radiographs can be accurate in showing air-fluid levels, but the degree of chronic inflammatory disease present is consistently and substantially underestimated (3). Unlike conventional radiography, CT clearly depicts the fine bony anatomy of the osteomeatal complexes.
Before the introduction of CT, complex motion tomography provided critical anatomic information, especially when bone destruction or bone displacement was in question. Contiguous sections can be as close as 1 mm apart in coronal or lateral projections to detail regions of interest after a preliminary screening examination has been performed with 3- to 5-mm contiguous sections, as in assessing a blow-out fracture of the orbital floor. This technique is used if CT is not available. Although it allows clear morphologic visualization of bony abnormalities, the conventional technique has a limited gray scale.
Computed tomography has been advocated for improved diagnosis and is considered the best method for evaluating the paranasal sinuses. Imaging in the coronal plane is recommended because it optimally displays the osteomeatal units, including the relation of the brain to the ethmoid roof and the relation of the orbit to the paranasal sinuses. Coronal images closely correlate with the surgical approach used in endoscopic sinus surgery. Axial images are recommended in addition to coronal images when a patient has severe disease in the frontal, sphenoid, or posterior ethmoid sinuses, especially if surgery in these regions is being considered. The initial CT scan should be obtained after an adequate course of medical therapy to eliminate reversible mucosal inflammation (4). Modern spiral CT scanners rapidly acquire thin axial images. Use of reformatted coronal images allows examination of pediatric patients and of patients who find it difficult to maintain the position needed for coronal imaging.
Inflammatory conditions, trauma, mucocele, and tumor are critical conditions in which the use of CT is mandatory. Understanding orbital-sinus and cranial-sinus relations is essential in assessing the pretreatment stage of carcinoma of the nasal cavities or paranasal sinuses, response to radiation therapy, or postoperative tumor recurrence. Axial examinations are essential for observing breaching of the posterior wall of the maxillary sinus. Although CT can be performed without contrast enhancement, enhancement can help differentiate obstructive secretions and a mass (MRI is most useful for this purpose). Tumor extension beyond the sinuses into the orbit, brain, or retromaxillary region is best seen with contrast enhancement.
Contrast enhancement techniques are important in evaluating vascular lesions. Angiofibroma of the nasopharynx necessitates use of this technique to identify the epicenter and extension of angiofibroma from the region of the sphenopalatine foramen, medially into the nasopharynx or laterally into the infratemporal fossa and anteriorly into the maxillary sinus or superiorly into the middle cranial fossa. Cerebrospinal fluid leak and meningocele are two neurogenic disorders that can necessitate intrathecal CT enhancement. Computer-generated three-dimensional CT images are being used increasingly in evaluating complex facial fractures and severe craniofacial anomalies. Computed tomography and MRI can be used intraoperatively during image-guided sinus surgery. Conventional radiographs, complex motion tomography, and CT have common radiographic signs (Table 6.5) (5).
Magnetic resonance imaging is most useful in the evaluation of regional and intracranial complications of inflammatory sinus disease, in the assessment of benign versus malignant sinus opacification. and in the evaluation of the extent of neoplastic processes (6,7). Compared with CT, MRI provides better visualization of soft tissue, but it does not optimally display the cortical air-bone interface. Therefore, CT is still a more reliable operative “road map” for a surgeon performing an endoscopic procedure on the sinuses. Staging systems are used to evaluate CT scans of the sinuses (8).
The introduction of MRI has influenced the diagnosis, management, and follow-up evaluation of tumors of the nasal cavities, paranasal sinuses, and nasopharynx. Magnetic resonance imaging is better than CT in the assessment or characterization of soft-tissue mass lesions. Magnetic resonance imaging depicts vascular structures without the use of intravenous contrast agents. Inflammatory lesions have high signal intensity on T2-weighted images, and tumor masses tend to have low or intermediate T2-weighted signal intensity. If MRI shows a noninflammatory mass, biopsy should be strongly considered.
Other diagnostic modalities used to study the paranasal sinuses have lesser but selective importance. Ultrasonography of the maxillary and frontal sinuses has limited usefulness but can help identify fluid when conventional radiographs show opacification. Radionuclide bone scans with technetium 99m methylene diphosphonate depict osteoblastic activity in several situations, particularly identification of focal manifestations of systemic disease, such as Paget disease. Detection of these nonspecific findings is highly sensitive, and the bone scan technique shows physiologic changes before morphologic studies with conventional radiographs and CT scans do. Gallium citrate scans, if used in combination with bone scanning, allow diagnosis of osteomyelitis and follow-up assessment of the effectiveness of treatment. Treatment is considered successful when results of a gallium scan return to normal. This modality specifically images the infective focus, unlike bone scanning, which images the osteoblastic response around the infective focus (9).
Soft Tissues of the Neck
Head and neck masses have traditionally been classified as benign or malignant, primary or metastatic, and congenital or inflammatory. This classification is further extended to cover age groups, such as children and adults, and location, such as midline and lateral, anterior triangle and posterior triangle. Although the most important preliminary step in evaluating neck masses is a careful physical examination of the neck and all mucosal surfaces, this often only establishes a working diagnosis or defines an outstanding clinical problem (Table 6.1). The uncertainty associated with clinical diagnosis is determined by limitations in differentiating solid and cystic lesions and in determining anatomic associations. Radiologic imaging is essential in responding to these clinical problems.
Conventional plain radiographs are not usually helpful in differentiating neck masses, except for recognizing infrequent signs such as calcification. Ultrasonography is a safe, relatively inexpensive, and readily available investigative method. Ultrasonography is categorized as high-resolution real-time imaging or as Doppler-based technique used to assess flow characteristics of the major blood vessels of the neck. Palpable lumps in the neck can be assessed with ultrasonography, which can be used for specific assessment of growth (size of lesion over time); location; relation of lesion to the adjacent structures, especially blood vessels; character of the lesion (solid, cystic, complex); and the number and size of affected lymph nodes in the region. Applications of ultrasonography include assessment of thyroglossal duct abnormalities, branchial cleft cysts, cystic hygroma, major salivary gland tumors, inflammatory processes that progress to abscess formation, and carotid body tumors, lymph node staging, and imaging-guided FNA.
Ultrasound techniques combined with FNA and cytologic evaluation have particular importance in the assessment of the soft tissue of the neck (10). The superiority of ultrasonography is only in its nonradiographic guidance capability including FNA biopsy of cervical lymph nodes or other masses. Ultrasonography also can be useful for percutaneous drainage of cervical abscesses. Fine needle aspiration biopsy guided by computed tomography can be used to diagnose poorly accessible or deep-seated lesions of the head and neck (11).
Computed tomography and MRI are widely used for primary staging of tumors and nodes. However, accuracy in assessing lymph nodes depends on the radiologic criteria used. Various criteria for the size of lymph nodes have been used for diagnosing metastatic lymphadenopathy, but the most reliable imaging finding is the presence of nodal necrosis. Areas of central nodal necrosis larger than 3 mm are routinely identified on contrast-enhanced CT scans. The usefulness of MRI and CT in the detection of lymph node metastasis from squamous cell carcinoma of the head and neck was assessed by Curtin et al. (12). Computed tomography performed slightly better than MRI in the detection of lymph node metastasis. A high negative predictive value was achieved only when a low size criterion (5 to 10 mm) was used and was therefore associated with a relatively low positive predictive value. For example, with criteria of 1-cm size or an internal abnormality to indicate a positive node, CT had a negative predictive value of 84% and a positive predictive value of 50%. Magnetic esonance imaging had a negative predictive value of 79% and a positive predictive value of 52%. Ultrasonography is hampered by similar morphologic criteria, and only ultrasound-guided FNA biopsy can offer additional cytologic criteria that may be more reliable (13). Positron emission tomography with 18-fluorodeoxyglucose in the detection of cervical lymph node metastasis has been shown in several studies (14,15) to have a higher sensitivity and specificity than CT, MRI, or ultrasound-guided FNA biopsy.
Compared with MRI, CT is the best method for studying capsular penetration and extracapsular nodal extension. With contrast CT, extracapsular extension is identified with an enhancing nodal rim, usually with infiltration of the adjacent fat planes. Carotid artery invasion is an important prognostic indicator, and invasion of the adventitia is as important as greater degrees of arterial invasion. Detection of microscopic adventitial infiltration is beyond the scope of current imaging, but circumferential involvement of the artery by tumor is strong evidence that the artery is invaded.
Both CT and MRI are useful to evaluate for tumor recurrence and posttreatment changes in the care of patients with malignant tumors of the head and neck. Magnetic resonance imaging has advantages in differentiation between tumor and scar tissue, but edema after radiation therapy can make differentiation difficult. Radiation-induced changes lead to false-positive diagnoses for approximately 50% of patients (16). Criteria for recurrent or residual tumor include an infiltrative mass with high signal intensity on T2-weighted images and enhancement after administration of gadolinium on T1-weighted images. Computed tomographic criteria for recurrent or residual tumor include the combination of a circumscribed, infiltrative mass with contrast enhancement on CT scans. Positron emission tomography compares favorably with CT and MRI in the detection of recurrent or residual cancer (17).
Other methods for detecting tumor recurrence include thallium 201 single photon emission computed tomography (SPECT) and gallium 67 citrate whole-body scintigraphy. Mukherji et al. (1 found thallium 201 SPECT to be superior to CT for differentiating recurrent tumor from posttreatment changes. Murata et al. (19) found gallium 67 citrate whole-body scintigraphy especially useful for evaluation for recurrence and distant metastasis of squamous cell carcinoma of the head and neck.
Computed tomography is useful for detecting clinically occult primary cancer of the head and neck that causes cervical metastasis. Magnetic resonance imaging can better depict submucosal lesions in the areas of the tonsils, anterior floor of mouth, and base of the tongue. Magnetic resonance imaging should be performed first for a mass in the retropharyngeal or parapharyngeal space. In these locations, tumors of neural, vascular, or salivary origin should be suspected. Magnetic resonance imaging also should be performed if posterior extension into the airway, esophagus, or posterior deep muscles is suspected. With few exceptions, CT is better than MRI in depicting thyroglossal duct cysts, branchial cleft cysts, and cystic hygroma and in differentiating infection, inflammatory processes such as cellulitis, edema, and abscess.
Digital subtraction angiography and conventional superselective angiography are useful in the diagnosis of hemangioma, arteriovenous malformation, and paraganglioma. Intra-arterial embolization has important therapeutic applications as definitive treatment or before surgery.
Despite being hypovascular, nerve sheath tumors can become greatly enhanced on CT scans, apparently because of extravascular leakage of contrast material into the tumor bed. Nerve sheath tumors have intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Paraganglioma becomes intensely enhanced after intravenous administration of contrast material during CT and MRI studies. The characteristic salt-and-pepper appearance on MR images reflects the signal voids of many tumor vessels. However, signal voids do not occur with all paragangliomas, especially in those less than 2 cm in diameter.
Larynx
Radiologic imaging modalities are important in screening and in defining the deep dimension of a malignant tumor of the larynx. Although the larynx is readily accessible to direct visualization, including telescopic assessment, and biopsy, submucosal extension is not subject to direct visualization. If possible, imaging studies should be performed before biopsy to avoid confusion of tumor and local trauma. Vocal cord mobility defects, whether due to direct infiltration by tumor or involvement of the recurrent laryngeal nerve, can be assessed with diagnostic imaging. There also are difficult-to-evaluate regions, such as the Morgagni ventricle or the subglottis. Imaging is critical in the evaluation of carcinoma of the larynx in all three major regions (supraglottis, glottis, subglottis) and in evaluation of extralaryngeal extension of malignant growth to the hypopharynx or the laryngeal cartilage. Virtual endoscopy of the airway is possible, but it has limited usefulness in differentiating mucosal surfaces that are touching (20).
Conventional plain radiographs (lateral and anteroposterior projections and selective high-kilovoltage filtration techniques) of the larynx provide preliminary or definitive information about foreign bodies, trauma, and other types of acute and chronic airway obstruction. These radiographs can show soft-tissue swelling, alteration of the cartilaginous framework if sufficiently calcified, and the position of the air column. The variability of calcification of the laryngeal cartilage can pose a diagnostic problem in the detection of foreign bodies. For example, the superior margin of the cricoid cartilage calcifies long before the signet portion does. The result is linear calcification on plain radiographs that often is mistaken for a foreign body.
Xeroradiography, because it provides edge enhancement, can clarify intrinsic soft-tissue detail such as calcification, delineate masses and stenosis, sometimes depict cartilage abnormalities such as fractures and erosions, and help identify foreign bodies by type and location. Unfortunately, this technique carries a radiation exposure three to five times that of conventional radiography. The usefulness of xeroradiography in imaging of the soft tissue and cartilage has been superseded by that of CT and MRI.
Conventional coronal tomography allows visualization of frontal view anatomy without a superimposed spine. Thus it allows satisfactory analysis of the vertical extent of laryngeal tumor and subglottic or tracheal stenosis or stricture. This technique has been replaced by CT and MRI because of its limited gray scale for soft-tissue differentiation, but the airway image, especially with the added sagittal projection, is excellent. Tomography has several limitations, such as poor definition of the anterior commissure. Depiction of cartilage invasion is unreliable, except when there is extensive involvement of well-calcified cartilage.
Ultrasonography has limitations because the laryngeal cartilage reflects most of the sound, limiting ultrasonic access. Nuclear medicine imaging seldom is useful for laryngeal imaging. Increased uptake has been mentioned as a cause of inflammatory arthropathy and relapsing polychondritis. Erythrocyte-tagged imaging can provide enough information for diagnosis of the rare laryngeal cavernous hemangioma. Arteriography is seldom used except for evaluation of a suspected vascular lesion such as paraganglioma.
Technologic advances in CT and MRI have greatly improved the ability to image the larynx. Spiral CT and fast MRI techniques allow rapid acquisition, which decrease degradation motion artifacts from breathing, swallowing, and carotid artery pulsation. Both CT and MRI allow evaluation of the extent of laryngeal tumors, especially for tumor size staging of carcinoma. Such determinations can influence the extent of laryngectomy (partial versus total).
Spiral CT scanners acquire the complete data set through the larynx in less than 10 seconds, allowing the patient to stay motionless. Images can then be reconstructed to give overlapping sections, and coronal, sagittal, and even three-dimensional images can be generated from the same data set. Examination of the larynx during various inspiratory-expiratory cycles has been used to optimize visualization of a particular region or the margin of a tumor. With operator-directed imaging, CT provides accurate images of the location, size, and extent of the tumor. Computed tomography can depict cartilage invasion and deep soft-tissue spread into the paraglottic space, preepiglottic space, and pyriform sinuses. This T-stage imaging contributes to a more rational diagnosis and more effective planning of surgical and radiation treatment.
The larynx has been difficult to image well with MRI because of motion artifact. Fast spin echo imaging has made a marked difference in the ability of MRI to image the larynx by reducing these motion artifacts. The use of gadolinium is controversial. Some experts believe gadolinium enhancement provides important information regarding the interface of tumor with muscle. However, fast spin echo imaging can generate similar information, obviating administration of gadolinium. Magnetic resonance imaging is better than CT at separating soft tissues. Another advantage of MRI over CT is acquisition of high-resolution images in multiple planes. Sagittal images show the epiglottis, vallecula, and base of the tongue well. Coronal views are ideal for evaluating the margins of the vocal cords, the paraglottic space, and the vertical extent of tumor. Axial images allow assessment of cartilaginous erosion.
The appearance of the cartilage on CT scans and MR images varies with the degree of ossification, which is not uniform and frequently is asymmetric. Invasion of cartilage has implications in staging and outcome of carcinoma of the larynx. With CT, tumors often have the same attenuation as nonossified cartilage (soft-tissue density), so minimal cartilage involvement can be difficult to assess. Gross cartilage destruction with tumor on the opposite side of the cartilage from the primary lesion is the only truly reliable CT sign of cartilaginous invasion. This finding is similar in MRI, but there is evidence to suggest that lesser degrees of tumor involvement can be detected with MRI because of variability in the appearance of both normal and abnormal cartilage afforded by MRI sequences. Nodal staging can be dramatically improved with sensitive broadening of the primary CT examination. Thin-section CT added to the primary tumor assessment can show enlarged or metastatic nodes in the neck and specific anatomic and pathologic features.
Salivary Glands
The diagnosis of salivary gland disorders is established from the findings of the history, physical examination, and FNA biopsy rather than from radiographic studies. However, imaging studies often are needed to assess focal, multifocal, diffuse, and bilateral disorders. New diagnoses, such as stones, can be readily established. Imaging studies can be used to confirm a clinical suspicion, such as human immunodeficiency virus–positive status from parotid gland enlargement with lymphoepithelial cysts.
Conventional radiographic examination that includes occlusal radiography and panoramic tomography can depict radiopaque duct calculi. Most submandibular duct and gland stones are radiopaque. Parotid duct stones occur infrequently and usually are radiolucent. Conventional sialography once was the standard method of assessment of the morphologic features of the salivary duct and glands. It is not commonly performed now, although it provides important information about nonopaque stones, ductal stenosis, sialectasis, and sialosis.
In imaging of the major salivary glands, ultrasonography has reasonable accuracy in differentiating intracapsular and extracapsular lesions. It also images solid and cystic lesions. Mixed solid-cystic lesions, such as Warthin tumor, are considered solid. Ultrasonography is limited in depicting deep-lobe parotid lesions because of the attenuation and reflection of sound by the mandible.
Radionuclide scanning is useful in some pathophysiologic salivary gland assessments because 99mTc-pertechnetate is incorporated into the salivary glands and excreted in the saliva. Increased focal uptake is characteristic of functioning tumors, such as Warthin tumor of the parotid gland and the rare oncocytoma. Diffuse, increased radionuclide uptake often indicates ductal obstruction leading to intra-acinous salivary retention in the presence of long-standing inflammation. Positron emission tomography does not reliably differentiate benign from malignant tumors, limiting its clinical usefulness. It also is expensive and takes a long time to perform.
Computed tomography and MRI are excellent methods for imaging and evaluating salivary gland disease, specifically focal, multifocal, and diffuse masses. The two modalities have equivalent diagnostic potential for imaging solid and cystic lesions. Both provide important information about the location (intraglandular or extraglandular), size, and extension of tumor to surrounding superficial and deep structures.
Bone invasion is viewed differently with MRI and CT, and marrow invasion of the mandible is better identified with MRI. The excellent soft-tissue depiction with MRI allows identification of the intraparotid portion of the facial nerve and its relation to infiltrative masses, which allows planning of surgical management. Magnetic resonance imaging also is superior to CT in evaluating the muscle-tumor interface. Another advantage of MRI over CT is the absence of exposure to radiation or the intravenous administration of iodine-containing contrast medium.
The choice of which imaging study to perform in investigating salivary gland disease is influenced by clinical presentation, user preference, and familiarity with a specific modality. Computed tomography is the choice in cases of inflammatory disease of the salivary glands, because MRI does not depict ductal dilatation or salivary calcification. However, if the clinical finding is a mass, the initial imaging evaluation, if any, usually is MRI. Computed tomography is an acceptable alternative, and ultrasonography can be used as a complementary study.
Thyroid Gland
The superficial position of the thyroid gland in the neck enables easy access for clinical examination and FNA. A wide range of high-technology imaging modalities are available for the diagnosis and management of thyroid disease. These may generate structural information, as do ultrasonography, CT, and MRI, or show tissue function, as does radionuclide scanning (21).
Conventional radiography is not a primary study. It is limited to screening for airway or esophageal displacement or invasion and to identification of calcification in the thyroid gland. Radionuclide scanning often is chosen for imaging malignant lesions of the thyroid. Three radioactive pharmaceuticals are commonly used in clinical practice. Sodium 99mTc-pertechnetate is trapped by the thyroid gland but is not organified. Radioiodine isotopes (iodine 123 and iodine 131) are trapped and organified by the parenchyma of the thyroid gland. Pertechnetate is the most commonly used radioisotope, at least for the initial evaluation. It is less expensive than radioisotopic iodine, is readily available, and approximates iodine trapping through the metabolism of the pertechnetate anion, which is not incorporated into hormonogenesis. Because 123I radioiodine scanning is unique in providing anatomic images and images of the functional activity of the thyroid gland or ectopic thyroid tissue, it is useful in a variety of clinical situations. These include investigation of a palpable thyroid nodule or a mass in the midline of the neck, base of the tongue, or mediastinum. Radiopharmaceuticals can be used in the management of cancer and Graves disease and in screening for thyroid metastasis and postsurgical recurrent tumor.
Radionuclide scanning has several limitations. The anatomic imaging resolution is only 1.0 cm, which restricts detail and definition. Scans may not give an adequate image of thyroid tissue if the patient is taking oral thyroid hormone supplements. A hot nodule on a sodium 99mTc-pertechnetate scan may or may not indicate a functioning tumor. In these situations, a radioactive iodine (123I) scan shows physiologic hormonogenesis and a functioning or nonfunctioning mass.
High-resolution ultrasonography is the first-line structural investigative modality in the diagnosis of many thyroid disorders, especially nodular disease. It is safe, inexpensive, simple, quick, and reproducible. Marked improvement in image quality occurred with the introduction of small-parts ultrasonography. Ultrasonography has an accuracy greater than 90% in differentiating cystic and solid thyroid nodules. Mixed solid-cystic nodules should be managed as solid masses. Ultrasonography can depict questionable or difficult-to-palpate lesions and can be used to direct FNA. It also can show whether a palpable nodule is part of a focal, multifocal (multinodular goiter), or diffuse process. Ultrasonography can be used to follow the size of a nodule after suppression therapy or cyst aspiration. The major limitation of ultrasonography is the inability to differentiate malignant from benign lesions on the basis of tissue characteristics. This is appropriately left to a pathologist. Retrosternal thyroid cannot be evaluated because of the bony interference with sound.
Computed tomography and MRI have similar roles in the evaluation of thyroid disorders and are essentially second-line imaging modalities for this region of the neck. Both techniques provide useful information about the size, shape, and anatomic structure of thyroid nodules. They can help determine whether a mass is solitary or part of a multinodular lesion. Computed tomography and MRI can be used to evaluate mediastinal, substernal, or retrosternal extension of thyroid masses and regional lymph node involvement or local recurrence. Computed tomography shows calcification better than does MRI, but MRI is superior in providing soft-tissue detail, especially for the muscle-tumor interface. Magnetic resonance imaging can be performed without intravenous contrast medium and does not expose the patient to radiation. If iodinated contrast material is used during CT, the iodine interferes for months with thyroid function tests and uptake of iodine 131 used postoperatively to manage well-differentiated malignant disease of the thyroid.
Parathyroid Glands
Parathyroid imaging is controversial in terms of the indications for imaging and the imaging agent used. Preoperative imaging localization studies are not performed at many centers if the patient has not undergone surgical intervention (22). There are many options for imaging the parathyroid glands, including ultrasonography, CT, MRI, angiography and many nuclear medicine studies. Ultrasonography is the least invasive. Because of their small size, normal parathyroid glands are not usually detected with ultrasonography. However, parathyroid lesions larger than 0.5 cm in diameter usually can be identified in a careful study. In cases of hyperparathyroidism due to parathyroid adenoma, accurate localization is reported at a rate between 69% and 88% (23). Our success rate is greater than 90%. For perithyroidal parathyroid adenoma, ultrasonography is an excellent imaging choice, but acoustic impedance prevents adequate imaging behind air-filled structures (trachea) or bone (mediastinum).
No nuclear medicine agent is exclusively taken up by normal or adenomatous parathyroid glands. The agents that are taken up by both parathyroid adenoma and thyroid tissue (thallium 201 and 99mTc-sestamibi) are subtracted from agents that are taken up by thyroid tissue only (99mTc-pertechnetate and iodine 123). However, 99mTc-sestamibi imaging is commonly performed without subtraction because this agent washes out of the thyroid gland rapidly but is retained by parathyroid tissue and thyroid adenoma. Although these scans have limited value in detecting four-gland hyperplasia but have some usefulness in detecting asymmetric hyperplasia, diagnostic accuracy is reported at between 50% and 95% in cases of parathyroid adenoma (24).
Digital subtraction angiography relies on a single morphologic characteristic—the regional blood supply to a hypervascular gland. After the intra-arterial or intravenous injection of contrast medium, a computerized image-subtraction program eliminates unnecessary background information. This technique allows identification and localization of parathyroid adenoma in 60% to 70% of patients. This modality rarely is needed because sestamibi scans and ultrasonography are so successful. It may be useful in revision cases of hyperparathyroidism.
Normal parathyroid glands seldom are depicted on CT scans. Markedly enlarged glands can be detected with CT with a sensitivity of 50% to 88%. In the neck, an axial CT image is no more informative than ultrasonography. Computed tomography is limited by technical factors, such as inadequate resolution of lesions less than 1.0 cm in diameter, or by limitations in interpretation, such as mistaking a tortuous vessel, thyroid mass, or lymph node for an enlarged parathyroid gland. Use of iodinated contrast agents for differentiating blood vessels from adenoma or lymphadenopathy prevents subsequent imaging with iodine-based nuclear medicine studies for approximately 6 weeks.
Normal parathyroid glands usually are not identified with MRI. Magnetic resonance imaging with gadolinium enhancement can be useful for evaluating hyperparathyroidism refractory to the first surgical attempt at correction. T2-weighted MRI and gadolinium fat-suppressed T1-weighted scans show parathyroid adenoma as an area of high signal intensity against a dark, soft-tissue background. A review of the parathyroid literature up to 1993 showed that MRI had the highest sensitivity for the detection of adenoma (74%) followed by nuclear medicine studies (72%), CT (65%), and ultrasonography (63%) (25). At reoperation for previously unidentified adenoma, MRI had the highest (66%). Ultrasonography had a sensitivity of 60%; CT, 48%; and nuclear medicine studies, 45%.

TRENDS IN DIAGNOSTIC PATHOLOGY

2009-02-07T06:28:00.000-10:00

New ideas regarding the use of diagnostic pathology in the evaluation of head and neck cancer parallel the introduction and use of novel techniques in other areas of diagnostic pathology. An increase in the use of molecular technology and the associated benefits that genetic information provides about the course of disease has had a definite effect on how pathologists and clinicians view disease. The opportunity to investigate the risk of adverse genetic events has greatly improved as knowledge of molecular biology grows. Traditional methods continue to be used to characterize oncologic processes. These morphologic approaches include electron microscopy, immunohistochemistry, and conventional histochemical staining. Although these methods provide diagnostic and prognostic information, they are being augmented with techniques that provide information on the genetic changes present within a tumor and the oncogenes and antioncogenes that influence biologic behavior. Use of these novel methods has contributed important information to the understanding of cellular differentiation and neoplastic development. As originally anticipated, not all information gained from these studies has been useful in defining the course of disease. Despite these limitations, valuable diagnostic and prognostic information has been gained with molecular technology. This information is currently being applied in protocol studies involving therapy for various malignant tumors, such as oncogene detection to define the course of squamous cell carcinoma of the head and neck. This chapter concerns trends in diagnostic pathology, provides current information on the molecular biologic aspects of head and neck cancer, and focuses on the use of molecular biologic investigations of this neoplastic process.
HUMAN GENOME PROJECT AND TECHNOLOGICAL DEVELOPMENT
The Human Genome Project was initiated in the 1990s to develop a comprehensive genetic and physical map of the human genome and to elucidate the complete DNA sequence of all human chromosomes. This project promises to provide new insight into the diagnosis and management of malignant diseases that affect humans. A highlight of the importance of this ambitious project is that it may become possible to obtain a genetic profile of all humans at birth. Issues related to the ethical use of this information have to be established, and use of this information has to be incorporated into standards of practice. In addition to identifying genes associated with cancer and other diseases, the Human Genome Project has led to the introduction of new terminology, contributed to the development of new technology, and provided novel ways to study cancer and other diseases. Genomics is the detection of genes associated with cancer and other diseases. Proteomics was introduced as a way to describe the study of the function of individual genes within the context of all genes in the cell at the protein level (functional genomics) (1). The proteome is defined as the expressed protein complement of a genome (2). The goal of proteomics is to develop a comprehensive, quantitative description of protein expression, which may include changes that occur during the development of tumors, dilated cardiomyopathy, or infectious disease and changes that occur after therapeutic intervention (2). Functional genomics also includes several terms such as transcriptome and physiome.
Laser capture microdissection was developed with the Human Genome Project (3). This was fortuitous because laser capture microdissection provides a mechanism whereby individual cells or groups of cells within tissues can be selectively removed and used for genetic analysis. The development of mouse models to study the effects of gene deletions and alterations or augmentation and the development of DNA microarray biotechnology concomitantly increased understanding and knowledge of mutated sequences in human tumors and their phenotypic expression. In concert with these methods or techniques, developments in computer technology and bioinformatics have contributed to the ability to evaluate the volume of data generated by these new technologies (4). The information that emerges from clinical trials will determine whether these studies improve understanding of the molecular anatomic and physiologic characteristics of normal and neoplastic cells. For example, investigators using a “lymphochip” to study lymphoma detected the complementary DNA (cDNA) arrays derived from mature lymphocytes and their precursors with the aim of determining the phenotypic expression of DNA alterations and the histologic type of lymphoma. With DNA microarray technology to analyze diffuse large cell lymphoma, two diverse phenotypes were found and were shown to have a profound influence on survival. Tumors with a profile of germinal B cells had a better overall response to treatment than tumors in which gene expression revealed activated B cells (5).
Information gained in the analysis of various types of tumors requires data from numerous patients. Individual differences, tumor heterogeneity, and novel methods to incorporate these findings into the current understanding of the multistage theory of cancer are necessary to ascribe genetic significance to the findings about a given tumor type. The goal of these studies is to tailor treatment to the genetic profile of a tumor. Paramount to these studies, however, is the need for continued advances in bioinformatics (4), the goal of which is to provide methods sufficient for data normalization and standards to provide statistical evaluation of the myriad data derived from these new technologies.
The use of laser capture microdissection in proteomics and genomic research has provided a method to selectively capture for analysis individual cells or groups of cells within tissues. In combination with DNA array technology (gene chip technology), in which large numbers of nucleic acid samples can be assayed, new advances are being made in the understanding of diseases that affect humans. With DNA chip technology, cDNA clone inserts are robotically printed onto a glass slide. They are subsequently hybridized to two different fluorescent labeled probes. The probes are pools of cDNA generated after isolation of messenger RNA (mRNA) from cells or tissues for comparative evaluation. The DNA probes are used to interrogate target sequences on the basis of specificity of hybridization to the known probe. The intensity and ratio of the fluorescent tag are measured, and the differences between the controls and the test samples are calculated to identify genes of importance in the test samples. An advantage of this technology is that it has produced a powerful method to evaluate the genetic composition of tissues from archival material and to document the genetic composition of tissues obtained from patients in clinical trials. The aim of this technology is to describe the multitude of genes expressed in a tumor, to develop genetic profiles of cancer among humans, and to tailor treatment to the genetic changes identified in a tumor sample.
p53 AND HEAD AND NECK CANCER
Molecular evaluation of malignant tumors that affect humans has included studies of cellular proliferation and oncogenesis in a variety of tumors, including tumors of the breast and prostate of adults and small blue round cell tumors of children. Most studies of oncogenes in head and neck cancer show a limited relation between oncogene activation and prognosis. No oncogene has achieved overall important measured against commonly used prognostic features. In some studies, however, when detection of an oncogene was combined with other prognostic indicators, a relation was shown between the presence of an oncogene and development and progression of cancer.
Considerable knowledge of the genetic nature of the biologic characteristics of tumors has emanated from studies of p53 (6). This tumor suppressor gene is located on the short arm of chromosome 17 (17p13.1). Wild-type p53 has a role in preventing accumulation of genomic abnormalities within cells that may lead to the development of a malignant phenotype. Mutations in p53 have been described in a variety of tumors, and this gene is commonly mutated in cancers that affect humans, including tumors of the head and neck region. Cytogenetic, molecular, and immunohistochemical methods have been used to study the role of p53 in carcinogenesis. Loss of the suppressor function of p53 most often is caused by complete loss of one allele associated with a point mutation in the second allele. The resultant mutated gene lacks the suppressor activity of the wild-type gene, is metabolically stable, and has a long half-life. Under normal conditions, p53 has a short half-life and may not be detected with current immunohistochemical methods. When p53 is mutated, altered forms can be found in 30% to 80% of tumors. The altered forms are more stable and are therefore easy to detect with immunohistochemical methods. p53 normally prevents cells with damaged DNA from progressing through the cell cycle in the transition from G1 into the S phase. This process allows the cell time to repair DNA damage. The importance of a functionally intact G1 cell cycle checkpoint is emphasized by the fact that cells lacking in wild-type p53 protein enter the S phase without having repaired the DNA. The result is progressive genomic instability followed by initiation of the malignant process. p53 acts as a transcription promoter and interacts with cellular proteins such as CCAAT-binding protein and the protein product mdm2 (7). Tumors associated with an abnormal p53 gene have been reported to be of high histologic grade and to have increased proliferative activity. In some studies, p53 mutations have been associated with shorter disease-free intervals and poor overall survival.
The role of p53 in the development of squamous cell carcinoma of the head and neck is not well established (Table 7.1). Reports in the literature support a role of this tumor suppressor gene in the evolution of cancer (8). However, in neoplasms involving the head and neck, the relation is unclear. Hamel et al. (9) reported that patients homozygous for the arginine allele at codon 72 of p53 had an increased risk of cervical cancer related to infection with the human papillomavirus (HPV). Despite the recognized association between epithelial cancer of the uterine cervix and HPV infection, no association was found between HPV infection and squamous cell carcinoma of the head and neck in an analysis of 163 cases. Other studies of oral squamous cell carcinoma and squamous cell carcinoma of the head and neck had similar findings (10). Of interest is the potential relation of cyclin D1 to the development of multiple primary neoplasms not associated with p53, the decreased median relapse-free survival time for p53-negative tumors, and the absence of a positive correlation between the Bcl-2 family of proteins and p53 in the genesis of tumors of the head and neck.

Gleich et al. (10) suggested that the genesis of squamous cell carcinoma of the head and neck is most likely mediated by a variety of pathways and that single genetic alterations are not sufficient to influence survival. Patients with tumors that have one genetic loss had a 2-year survival rate of 78%. Patients with tumors that had two or more genetic alterations had a median survival rate of 58%. Mutation of the p53 gene was not associated with survival but was believed to represent a clonal marker not susceptible to change during metastasis (11). Warnakulasuriya (12) stated that p53 mutations are not useful in predicting outcome for patients with oral leukoplakia and are not informative as a sole marker to predict tumor development among persons at high risk. Some studies, however, have shown that p53 has prognostic utility in predicting the biologic behavior of squamous cell carcinoma of the tongue. Unal et al. (13) suggested that p53 may have a role in the biologic behavior of squamous cell carcinoma of the tongue. They reported that p53 immunoreactivity correlates with tumor size, lymph node metastasis, and stage.
Kudo et al. (14) investigated the possible association between p53 and p21 (cyclin-dependent kinase inhibitor) in the development of oral epithelial dysplasia and squamous cell carcinoma. No association was found, but the authors suggested that the combination of p21 and p53 expression may play a role in prognosis among patients with oral dysplasia and carcinoma. Expression of p21 in oral squamous cell carcinoma may be related to cellular proliferation and mdm2 expression that is independent of p53 protein alterations. Lam et al. (15) found that p21 is associated with tumor stage, tumor grade, nodal status, and mitotic count. Their findings showed that p21 is an important factor in the progression of squamous cell carcinoma of the larynx and esophagus. Expression of p53, p21, Rb, and mdm2 proteins in carcinoma of the tongue was investigated in a study involving patients younger than 35 years and patients older than 75 years. The results suggested that there are no differences in expression of these gene products in carcinoma of the lateral aspect of the tongue (16). In laryngeal carcinoma, p27 expression was found to be an independent prognostic indicator. In predicting the development of cancer among patients with oral leukoplakia, several factors have been found to be associated with the development of cancer. These include oral histologic findings, cancer history, chromosomal polysomy, p53 protein expression, and loss of heterozygosity at chromosomes 3p and 9p.
MICROSATELLITE INSTABILITY AND HEAD AND NECK CANCER
Little information exists about the relation between microsatellite instability and oropharyngeal carcinoma. Lynch and Kaul (17) discussed microsatellite instability in colorectal carcinoma in an editorial accompanying a published report that documented the influence of microsatellite instability on the development of colorectal carcinoma. It was suggested that the colorectal carcinomas that had microsatellite instability were more likely to be indolent. However, the results were not statistically significant when compared with the Dukes classification of colorectal cancer. One study (1 showed that chromosome tetraploidization is important in malignant transformation of laryngeal tumors. In this study, most dysplastic lesions and carcinomas in situ contained chromosomal abnormalities. The time to development of cancer from baseline biopsy was shorter among patients with unstable chromosomal contents than among the group with stable chromosome contents.
Evaluation of 51 squamous cell carcinomas from various sites in the head and neck area revealed that overexpression of p53 correlated with an increased prevalence of chromosomal abnormalities and aneuploid tumor. A significant correlation was shown between tumors that had metastasized and ploidy. These findings showed that tumors with high rates of metastasis had increased chromosomal imbalances. Some studies have shown a poor correlation between microsatellite instability and risk factors associated with squamous cell carcinoma of the head and neck. On chromosome 9p, loss of heterozygosity targets the same region as documented in other tumor types. The suggestion is that the patterns of microsatellite instability documented in other types of tumors are similar. To document the role of loss of heterozygosity, 77 oral squamous cell carcinoma with 11 microsatellite markers located on chromosomes 3p and 9p were studied (26). Loss of heterozygosity was identified in multiple sites, and 44% of the tumors showed allelic loss at one or more loci on both 3p and 9p. No correlation was shown between the frequency of loss of heterozygosity and stage of disease.
HUMAN PAPILLOMAVIRUS AND SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
Human papillomavirus has a role in the genesis of squamous cell carcinoma of the head and neck (19,20). Approximately 20% of oropharyngeal tumors had the same type of or DNA similar to the type present in squamous cell carcinoma of the uterine cervix, perianal and anal skin, vulva, and penis. The results of these studies suggested that HPV might have a causal relation in some types of head and neck cancer. These results also suggested that HPV-positive tumors arising in the head and neck area have an improved prognosis (19).

ALLERGY AND IMMUNOLOGY

2009-02-07T06:26:00.000-10:00

Understanding immunology is fundamental to understanding the cause, diagnosis, and management of many diseases. A basic understanding of the immune system is essential for all physicians. Besides helping to understand disease processes, knowledge of the immune system is essential in the evaluation of recurrent bacterial infections. Most determinations in diagnostic immunology laboratories are based on well-established principles of antigen-antibody reactions. This chapter is an overview of immunology and the allergic response. The field of immunology continues to evolve rapidly, as indicated by the identification of more than 161 cluster of differentiation surface antigens and more than 18 interleukin molecules.
The immune system differentiates self and nonself. It identifies and destroys elements foreign to the body and recognizes and protects self components. Immune surveillance is the mechanism by which the immune system determines on a cellular and molecular level how to deal with foreign invaders or with deviations of self-constituents. If the immune system detects something foreign on a cell surface, a reaction aimed at eliminating that cell begins. The immune system is anatomically and functionally divided into three compartments—primary lymphoid organs that produce lymphocytes; lymph nodes and the spleen, which provide a microenvironment for efficient interactions between lymphocytes and antigens; and the extralymphoid or tertiary lymphatic tissues.
The cells primarily responsible for immune recognition are lymphocytes, which have surface-specific receptors for antigenic determinants, or epitopes, of foreign molecules. Because each lymphocyte bears several copies of the same receptor, the body needs millions of lymphocytes, each with different receptors, to recognize the myriad foreign substances that humans encounter during their lives.
The clonal selection theory of immune cell origin and development suggests that, first, specific antigens select only the appropriate lymphocyte clone and, second, the specificity of lymphocytes develops before the introduction of antigen. When an antigen contacts and binds to a receptor, the lymphocyte becomes activated and then proliferates. Proliferation or clonal expansion leads to production of a large number of lymphocytes with the same receptors as those of the parent cell. If the body contacts the same antigen in the future, the number of cells that can recognize it increases, and the reaction becomes faster and more effective; that is, there is a positive immunologic memory. Sometimes the first exposure to an antigen reduces the likelihood of a response to a second stimulus; that is, there is negative memory or immunologic tolerance. The other transformation that lymphocytes undergo is differentiation, by means of which they initiate protein synthesis of lymphokines and antibodies.
The immune system has nonspecific effector mechanisms that amplify the specific responses—the innate immune system (1). These nonspecific features include the response of mononuclear phagocytes, polymorphonuclear leukocytes, and the complement system as well as enzymes, such as lysozyme, physiologic mechanisms, such as ciliary motion, interferons, and proteins, such as acute-phase proteins.
DEVELOPMENT OF THE IMMUNE SYSTEM
The cells involved in immune reactions are derived from pluripotential hematopoietic stem cells (2). These pluripotential stem cells arise from the bone marrow and give rise to precursors in the erythroid, myeloid, and lymphoid lines. Molecules known as cluster of differentiation (CD) on the surface of immune cells serve to identify subpopulations, and they function in cell differentiation. For example, marrow hematopoietic stem cells display CD34, whereas T cells can display CD2, CD3, CD4, CD5, CD6, CD7, CD8, or CD28. The lymphoid precursors become either pre-B or pre-T cells.
Mature B cells have antibodies on their surface that act as antigen receptors. During early stages of development, B cells are inactivated by contact with self components (clonal abortion). Mature B cells, which escape clonal abortion, leave the bone marrow and migrate to germinal centers within the lymphoid follicles of lymph nodes and the spleen.
Pre-T cells initially travel from the bone marrow to the thymus to complete their maturation. Prethymocyte receptors are generated by random gene arrangements and must bind to class I or class II antigens of the major histocompatibility complex (MHC) to survive. Cells that do not recognize self (MHC) are destroyed, as are cells that bind too tightly to the MHC (these have potential for inducing autoimmune disease). Maturation involves interactions among T cells, thymocytes, and maturational hormones such as thymosin, thymopoietin, and thymulin, produced by the thymic stroma. There are positive and negative selection mechanisms for immature T cells, which maximize their functioning. Positive selection is mediated by termination of each cell by programmed cell death (apoptosis), which proceeds through intracellular messages. If there is little or no binding of the T-cell receptor (TCR) to the peptide-MHC complex, apoptosis ensues, and the cell is eliminated. The mature T cells leave the thymus and become localized in the deep cortex of lymph nodes and in the perivascular areas of the splenic medulla. This distribution optimizes interaction among T cells, B cells, and macrophages.
Lymphocytes (mainly T cells) recirculate between lymph nodes, blood, lymphatic channels, and some organs, providing immune coverage of the whole body. The process in which immune cells migrate into areas of inflammation is vital to host defense. Coordination of the sometimes rapidly fluctuating relocation of immune cells involves a number of molecules. For lymphocyte migration from the bloodstream, integrins (glycoproteins) on the cell surface mediate cellular attachment to endothelium. Inflammation incites endothelial cells to signal lymphocytes to activate their integrins by elaborating a family of molecules called chemokines. When an immune cell surface receptor contacts its complementary antigen, the activity of molecules involved in adherence to endothelium greatly increases. Once the lymphocyte adheres to endothelium, it “rolls” along the vessel, allowing sustained membrane contact. The rolling feature is mediated through an interaction of selectins, which are another family of surface glycoproteins on immune cells. After exhibiting the rolling feature, the cell penetrates between endothelial cells. Extracellular matrix proteins (fibronectin, laminin), intercellular adhesion molecules (ICAM-1), fibrinogen, and vascular adhesion molecules (VCAM-1) mediate cellular movement through tissue.
The process of cellular adhesion is similar to the complement cascade, in which one molecular interaction follows another, and the final outcome can be disrupted by the ineffectiveness of any step. Understanding adhesion of lymphocytes and of other circulating cells provides several approaches to inhibition of this cascade. These include receptor-ligand binding by monoclonal antibodies, binding of small molecules to ligands, and antisense oligonucleotides to target endothelial cell adhesion molecules and to inhibit nuclear factor-kb, which regulates gene expression of several adhesion molecules, such as ICAM-1, VCAM-1, and E-selectin. These approaches must balance the importance of adhesion in host defense against the tissue damage induced by an overzealous response. Persons deficient in adhesion molecules are at risk of severe bacterial infection.
CELL-MEDIATED IMMUNITY
Monocytes, macrophages, dendritic cells, Langerhans cells, and B cells can function as antigen-presenting cells (APC), in which engulfed antigens, such as proteins, viruses, and bacteria, are partially degraded in their phagolysosomes and presented on the cell surface (3). Fragments of these antigens reappear later on the phagocyte surface. With its receptor, the T cell recognizes both the presented antigen and the markers of self (MHC) attached to the phagocyte surface. These markers of self originate in the MHC, located on chromosome 6.
Two kinds of MHC antigens exist. Class I is composed of two polypeptide chains, one constant from person to person and the other highly variable. Class I antigens appear on the surface of all nucleated cells in the body and have CD8 as the TCR. Class II antigens, composed of two variable polypeptide chains, are present on the surface of APCs and B cells and have CD4 as the TCR. Major histocompatibility complex antigens can be induced (class I) or repressed (class II) by the same cytokine (small proteins). This shows that cells can have differential responses to the same immune mediator. Cytokines are released from the APCs and alter the immune function of the presenting cell and other cells in the immediate area. For example, interleukin-1 (IL-1), which is primarily monocyte-macrophage derived, stimulates proliferation of B cells and some T cells, hematopoiesis, and synthesis of tumor necrosis factor a (TNF-a). The redundancy of cytokine functions combined with their proinflammatory and anti-inflammatory activities makes it difficult to understand the role of these substances in disease.
Antigens on the surface of APCs contact helper T (TH) cells. The TH cell recognizes foreign antigens and class II MHC antigens. To become activated, a TH cell needs not only antigen and MHC binding but also IL-1, a growth factor produced by the APCs. Costimulatory molecules binding through CD40 also play a role. The TH cell secretes other growth factors, such as IL-2, which can stimulate the TH cells to exhibit IL-2 receptors on their surface. The up-regulation of IL-2 receptors produces an amplification mechanism. Most immune responses require soluble growth and differentiation factors such as IL-2. Persons deficient in these factors have severe impairment of the immune system.
Helper T cells have been classified into subsets, TH1 and TH2, on the basis of their distinct lymphokine secretion profile and function. The TH1 clones secrete IL-2, IL-3, IL-6, IL-10, TNF-a, TNF-b, interferon-d (IFN-d), and granulocyte-macrophage colony-stimulating factor (GM-CSF). They also proliferate in response to antigen presented by both B cells and macrophages without a requirement for IL-1. Helper T cells in subset 1 induce IgM, IgG, and IgA but not IgE responses, and they stimulate cell-mediated immune responses such as eradication of intracellular bacteria and viruses and delayed-type hypersensitivity. The TH2 clones proliferate suboptimally in response to antigen presented by B cells, unless IL-1 is added. The TH2 clones, which secrete IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, TNF-a, and GM-CSF are more effective than TH1 clones at assisting antibody secretion. In particular, IL-4 and IL-13 promote the switch of B cells to IgE production. The cytokine microenvironment and the type, amount, and site of antigen exposure affect the type of TH cell that develops. Helper T cells in subset 2 have been recovered from nasal and bronchial tissues of patients with allergies after antigenic challenge. The differentiation of TH0 cells to TH1 or TH2 cells may explain how different immunization conditions can preferentially or selectively induce either humoral or cell-mediated immune responses, and it may explain distinct patterns of disease, such as the polar forms of lepromatous and tuberculoid leprosy. The switch from a TH2 cell to a TH1 cell response has been postulated as the mechanism underlying effective allergen immunotherapy and the reason for the increasing prevalence of allergic rhinitis (4).
Delayed-hypersensitivity T cells (TDH cells) also recognize antigen. Along with class II MHC products, TDH cells become activated by IL-2 and secrete lymphokines. Some of these lymphokines activate and attract macrophages, which ingest and destroy the antigen. This is the basis of skin testing for evaluation of delayed hypersensitivity. Antigen, such as tuberculin, mumps vaccine, or candida, is injected intradermally. If the antigen is recognized, local inflammation occurs, and cytokines are released that increase expression of the adhesion molecules ICAM-1 and VCAM-1 on the vascular endothelium. Adhesion molecules and surface molecules on TDH cells, such as very late activating antigen 4 (VLA-4), interact during T-lymphocyte movement to the area. The site becomes indurated 24 to 48 hours later. A positive response means that the patient has adequate APCs in the skin, as well as adequate numbers of functioning TDH cells and macrophages. CD8 T lymphocytes, like CD4 T lymphocytes, have been shown to have subsets (Tc1 and Tc2). Tc1 cells secrete IFN-g, and Tc2 cells secrete IL-4. The role of these cells is just beginning to be appreciated.
Cytotoxic, or killer, T cells (TC cells) recognize antigen coupled to class I MHC products (4). They kill the body’s own cells that have undergone change, such as viral or malignant transformation. For activation, TC cells must recognize a class I MHC plus antigen specific for virus and then get help from TH cells. Once activated, the TC cells circulate in the body and kill all cells that bear the new antigen through the transfer of cytolytic compounds (perforin and granzymes). Perforins and granzymes primarily destroy some viruses and intracellular bacteria, and they mediate rejection of grafts and tumors.
T cells can cause cell death (apoptosis) by binding to a molecule, Fas (CD 95), attached to the surface of most cells. Binding of Fas to its ligand leads to apoptosis of the cell expressing Fas through activation of an intracellular cascade of proteases. Fas molecules are involved mostly in tolerance induction and regulation of T-cell maturation. Fas expression on T and B cells increases after an encounter with an antigen. Fas ligand begins to be expressed on mature CD4 and CD8 T cells after activation. Toward the end of an immune response, they can induce apoptosis in cells that have up-regulated Fas. Abnormalities in this process are responsible for a childhood disorder of lymphoproliferation and for autoimmune thyroiditis. Fas ligand also is permanently expressed in the eye and testis and is thought to be responsible for immune privilege at these sites. That is, anatomic sites where transplanted foreign tissues survive for an extended time in a person with normal immune function. How tumors provide their own environment of immune privilege is an active area of investigation (5).
Suppressor T cells (TS cells) also participate in the normal regulation of immunity. Their role in human immunology, however, has not been defined precisely. They probably down-regulate TH cells and secrete suppressing lymphokines in an antigen-specific or nonspecific manner. Evidence suggests that excess TS cell function occurs in some immunodeficiency states, whereas TS cell deficiency occurs in some autoimmune diseases (6).
gdT cells play a role in microbial immunity. Although the precise role is not defined, these cells appear to be involved in terminating the host immune response to infection and preventing chronic disease. After activation, gdT cells acquire cytotoxic activity and kill stimulatory macrophages (7).
Unlike TC cells, which appear in the tissues in response to antigen, another class of killer cells, called natural killer (NK) cells, does not depend on previous immunization. They kill some types of tumor cells, primarily of the hematopoietic system, by means of release of perforins and proteases and by means of induction of apoptosis. It is possible that they regulate lymphocyte development and that their ability to kill tumors represents a cross-reaction. In animals, tumors that are not susceptible to NK cells have greater malignant potential than do NK-susceptible tumors. The activity of NK cells increases greatly with exposure to interferon. These cells have an as yet undefined role in the control of viruses, bacteria, and parasites. Natural killer cells lyse specific cells when antibody is present, a method termed antibody-dependent cellular cytotoxicity. Natural killer cells look like large, granular lymphocytes, but differ from mature T cells or B cells. They display CD2, CD16, and CD56 markers, which are not classic B-cell and T-cell markers, and they do not express surface immunoglobulins. Most can be identified by the monoclonal antibody Leu-11. Interleukin-2 causes activation and proliferation of NK cells, now called lymphokine-activated killer cells (LAK cells), which exhibit antitumor activity (8).
T-cell receptors for antigen are unique markers on the surfaces of T cells and are heterodimers. Monoclonal antibodies to these surface markers can identify T cells and their subpopulations. For example, CD3 and CD2 are antibodies that recognize all T cells, whereas CD4 identifies helper and TDH cells and CD8 identifies cytotoxic and suppressor T cells. T cells represent about 65% of lymphocytes in the peripheral blood. Unlike B-cell receptors, which increase their affinity to antigens by means of mutation, TCRs do not. Genetic recombinations of TCRs can produce a nearly infinite number of antigen receptors. This is important in the distinction between self and nonself (a T-cell function) and in prevention of autoimmunity. Once processed, antigen and associated MHC bind TCR, and CD22 on B cells binds CD45 on T cells, which activates intracellular phosphatyrosine phosphatase. This activates tyrosine protein kinase, which phosphorylates components of the CD3 complex and leads to hydrolysis of membrane phosphoinositides. The diacylglycerol and inositol 1,4,5-triphosphate produced then act as second messengers to mobilize calcium. This activates protein kinase C, which phosphorylates other proteins, and this causes the genetic effects that produce cell activation and elaboration of proteins.
T-cell receptors do not bind soluble antigen as do their antibody counterparts on B cells. Instead polypeptide antigens are internalized and processed by special APCs, which give rise to short peptides. These bind to molecules of the MHC, and the combination is recognized by the TCR. Superantigens, powerful microbial toxins, produced by Staphylococcus aureus and Streptococcus pyogenes organisms cause fever and shock by binding to class II MHC and TCR molecules. Binding to HLA-C antigen inhibits the lytic capability of NK cells. T cells have a graded response to antigens from activation to complete unresponsiveness.
HUMORAL IMMUNITY
Unlike T cells, B lymphocytes (B cells) have numerous receptors that bear striking similarities to the immunoglobulin molecules they later secrete. These receptors initially belong to the IgM and IgD classes, but later shift to IgG, IgA, or IgE. Each receptor reacts to one antigen, so millions of B cells are needed to ensure proper immune function. Unlike T cells, B cells do not need the joint recognition of self-markers and antigens (9). Eighty percent to 90% of all immunoglobulin-producing cells are located in the mucosa and exocrine glands. The adhesion molecules a4b7 and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) appear important in localizing B cells to these areas (10).
Some antigens can directly activate B cells (T-independent antigens), whereas other antigens require T-cell cooperation (T-dependent antigens). In T-dependent activation, the B cells first contact antigen through IgM and IgD molecules on the cell surface, then process and present the antigen. The processed antigen later appears on the surface of the B cells in association with class II MHC. An antigen-specific T cell binds to this combination with the help of several membrane proteins (TCR, class II MHC, leukocyte function-associated antigen 1 [LFA-1], and ICAM-1). The activated T cell then expresses gp39, which binds to CD40, a membrane protein on B cells, and which is a potent mitogen receptor. With the assistance of lymphokines, the B cell begins to proliferate and differentiates into an antibody-secreting cell (plasma cell) that no longer carries immunoglobulins on its surface. However, a percentage of B cells that have been clonally selected remain as memory cells. These cells possess a high density of high-affinity surface immunoglobulins, usually of the IgG, IgA, or IgE class. T-dependent activation occurs with complex antigens, because the antigenic determinants are not accessible to the B cell because of stereometric hindrance, forcing the antigen to be processed before being presented.
T-independent antigens have large structures with repeating antigenic determinants (epitopes), such as carbohydrates, which can cap and bridge immunoglobulins on the B-cell membrane. This mode of B-cell activation is inefficient and provides primarily IgM antibodies, because the isotype switch from IgM to IgG production in the same B cell requires T-cell factors such as IL-4 and IFN-d. Isotype switching is mediated by specific genetic rearrangements and maintains antigenic specificity. Independent antigens include carbohydrates from the capsule and cell wall components of bacteria. They do not include most protein antigens. This may explain why patients with severe compromise of T-cell function maintain antibody levels to bacterial pathogens.
IMMUNOGLOBULINS
Immunoglobulins are glycoproteins composed of 82% to 96% polypeptide and 4% to 18% carbohydrate components (2) (Fig. 8.1). They account for approximately 20% of the total plasma proteins. All immunoglobulin molecules contain an equal number of heavy (H) and light (L) polypeptide chains. Each polypeptide chain consists of a number of domains of constant size (100 to 110 amino acid residues) linked by intrachain disulfide bonds. The N-terminal domain of each chain, designated as variable region (Fab), shows more variation in amino acid sequence than does the C-terminal end (constant region, Fc). The antigen-binding site of the antibody molecule represents only a small number of amino acids in the V regions of H and L chains. However, because a number of gene segments can combine to form new V, D, and J segments, a nearly unlimited number of antigenic specificities are possible. These amino acids are brought into close relation by the folding of the V regions. Covalent interchain disulfide bridges hold the chains together and form a bilateral symmetric structure. The polypeptide chains fold into globular regions called domains. The domains in H chains are designated VH (variable region of heavy chain) and CH1, CH2, CH3, and CH4 (constant region of heavy chain), and those in L chains are designated VL and CL. Both ends of antibodies function in that the Fab portion (antigen-binding fragment) binds with specific antigens, whereas the Fc portion initiates a variety of secondary phenomena, such as complement fixation.
All of the L chains have a molecular weight of approximately 23,000 and can be classified into two types, k and l, on the basis of structural differences in constant regions. In humans, k chains outnumber l chains two to one. Any immunoglobulin molecule always contains identical k or l chains.
Five classes of H chains exist in humans. They are based on structural differences in the constant region. The different H chains, designated g, a, µ, d, and e, vary in molecular weight from 50,000 to 70,000. The µ and e chains possess five domains (one variable and four constant) rather than the four domains of g and a chains. The H chain determines the class of the immunoglobulin. There are five classes of immunoglobulins: IgG, IgA, IgM, IgD, and IgE. Most of the H-chain classes have been further subdivided into subclasses on the basis of differences in the constant regions. H chains representing the various subclasses, however, are much more closely related to each other than to the other immunoglobulin classes. There are four subclasses of g chains in humans, g1, g2, g3, and g4, which yield IgG1, IgG2, IgG3, and IgG4 subclasses of IgG molecules. In the same way, µ and a chains have two subclasses each.
Immunoglobulins are present not only in serum, but also in body secretions such as saliva, mucus, sweat, breast milk, and colostrum. Immunoglobulin A, the predominant immunoglobulin class in external secretions, usually exists in human serum as a four-chain unit of approximately 160,000 molecular weight. The IgA in secretions consists of two four-chain units associated with a secretory component and a J chain. The J chain, in contrast to the secretory component, is associated with all polymeric forms of immunoglobulins that contain two or more basic units. The presence of a J chain facilitates the polymerization of basic units of IgA and IgM molecules. Quantitative measurements indicate that there is a single J chain in each IgM pentamer or polymeric IgA molecule.
The secretory component, or polymeric immunoglobulin receptor, which mediates the transport of polymeric IgA, is an integral membrane protein expressed in the basolateral membrane of epithelial cells. From there, this receptor undergoes continuous endocytosis, is transported across the epithelial cell, and then is secreted at the apical membrane into mucosal secretions. Transport of polymeric IgA occurs after synthesis and secretion by B cells in the lamina propria (9). Polymeric IgA binds with high affinity to the SC on the epithelial cell and the complex is transported to mucosal secretions. Mucosal secretions therefore contain a mixture of secretory IgA and free secretory component, except in patients with IgA deficiency, who have only secretory component. Immunoglobulin M also can be transported by this process. Persons deficient in IgA often have a compensatory increase in secretory IgM.
Immunoglobulin G
In normal adults, IgG, which has the most prominent role in memory immune responses, constitutes approximately 75% of total serum immunoglobulin. The relative concentrations of the four subclasses are as follows: IgG1, 60% to 70%; IgG2, 14% to 20%; IgG3, 4% to 8%; and IgG4, 2% to 6%. IgG can cross the placenta and provides protection of the newborn during the first months of life. No other immunoglobulin has this property. Immunoglobulin G can fix complement, with the subclasses functioning unequally: IgG3 greater than IgG1, which is greater than IgG2, which is greater than IgG4. Immunoglobulin G4, although completely unable to fix complement by the classic pathway, can use the alternative pathway. Other complement components adhere to the bacterial surface and promoting phagocytosis through C3b receptors and through those that bind IgG1, IgG3, and their Fc fragments. The coating of the bacteria with antibodies (opsonization) makes it easier for phagocytes to capture them and increases the efficiency of phagocytosis several hundredfold. Immunoglobulin G is involved in cytotoxicity with NK cells. Antibody response to proteins yields primarily IgG1 and IgG3, whereas polysaccharides elicit mainly IgG2.
Immunoglobulin A
Immunoglobulin A, most of which is produced locally, predominates in body secretions. There are two subclasses, IgA1 and IgA2. The TH cells in the lymphoid tissues of the gastrointestinal and respiratory tracts switch the B cells from IgM to IgA secretion. Secretory IgA, because of its abundance in saliva, tears, bronchial secretions, nasal mucosa, prostatic fluid, vaginal secretions, and mucous secretions of the small intestine, provides the primary defense mechanism against local mucosal infection. Its main function may be to prevent access of foreign substances to the general immunologic system. Besides its traditional role in extracellular antibody function, IgA can neutralize viruses intracellularly, can provide an internal mucosal barrier by intercepting antigens and ferrying them through the epithelium, and after binding to the surface of some leukocytes can activate the alternative pathway of complement activation. Immunoglobulin A, however, is primarily believed to be an anti-inflammatory antibody. Immunoglobulin A normally exists in the serum in both monomeric and polymeric forms, constituting approximately 15% of total serum immunoglobulin.
Immunoglobulin M
Immunoglobulin M constitutes 10% of serum immunoglobulin and normally exists as a pentamer with a molecular weight of 900,000. Immunoglobulin M antibody predominates in the early immune response. Immunoglobulin M, with IgD, is the main immunoglobulin expressed on the surface of B cells. It is the most efficient complement-fixing immunoglobulin, but its huge size makes it dangerous in high concentration. The IgM response declines and is replaced by IgG of the same antigen specificity. Fetuses make IgM before birth, but maternal IgM does not cross the placenta. Immunoglobulin M antibody to a specific organism in newborn serum indicates intrauterine infection.
Immunoglobulin D
Immunoglobulin D is a monomer normally present in serum in trace amounts (0.2% of total immunoglobulin). The main function of IgD is unknown. Immunoglobulin D, with IgM, predominates on the surface of human B lymphocytes. Its most important role may be as a receptor.
Immunoglobulin E
Immunoglobulin E constitutes only 0.004% of total serum immunoglobulin, but it binds with high affinity to mast cells and basophils through the Fc region. When combined with allergens, IgE antibodies trigger the release of inflammatory mediators such as histamine from mast cells and basophils. Immunoglobulin E also binds to macrophages, platelets, and eosinophils by means of low-affinity receptors. Like IgD and IgG, IgE normally exists in monomeric form.
COMPLEMENT
The complement system is the primary humoral mediator of antigen-antibody reactions (Fig. 8.2) (11). It consists of at least 20 chemically and immunologically distinct plasma proteins, which can interact with each other, with antibodies, and with cell membranes. The biologic activity of complement is manifested in three ways. First, complement proteins bind or opsonize to particles. Specific cellular receptors for these complement proteins then mediate the binding and uptake of the opsonized particles by polymorphonuclear leukocytes and monocytes. Second, the small fragments of proteolytic cleavage from complement proteins diffuse readily and can bind to neutrophils and macrophages, causing chemotaxis and cell activation. Similar receptors on lymphocytes and APCs bind complement-opsonized antigen in the form of immune complexes and enhance specific immune responses. At least 12 regulatory proteins and at least five complement receptors regulate the function of complement. Third, complement causes lysis by the insertion of a hydrophobic “plug” into lipid membrane bilayers and allows osmotic disruption of the target. Deficiencies in complement frequently cause severe infection or autoimmune disease. Most of the proteins in the complement system are clustered on chromosome 1q and within the MHC region on 6p (12).
The proteins of this system circulate as functionally inactive molecules and compose approximately 15% of the globulin fraction of plasma. Many of these proteins are zymogens, that is, proenzymes that need proteolytic cleavage to acquire enzymatic activity. Each protein of the classic pathway and membrane attack complex is assigned a number, and the proteins react in the following order: C1q, C1r, C1s, C4, C2, C3, C5, C6, C7, C8, and C9. The proteins of the alternative pathway are assigned letters preceded by the letter F (factor).
Activation
The most important step in differentiation of self from nonself by complement is the covalent binding of C3 to particles. Bound C3 functions as an opsonin and as an inciter of lytic membrane attack. Cell surfaces contain molecules that effectively limit C3 deposition, whereas nonself surfaces allow rapid deposition of many C3 molecules. The second mechanism whereby complement differentiates self and nonself is specific direction of C3 deposition to antigen-antibody complexes.
The Classic Pathway
The classic pathway is the main antibody-directed mechanism for the triggering of complement activation. C1q binds to the CH2 domains of IgG in immune complexes or to the CH3 domains of a single IgM molecule, which has been modified by antigen binding. The next steps both amplify the response and concentrate the site of activation to the particle that initiated activation. C1s cleaves C4 into C4a and C4b. Zymogen C2 binds to C4b and is cleaved to C2a and C2b. C4b2b, the classic pathway C3 convertase enzyme, cleaves C3 into C3a and C3b.
Alternative Pathway
An initial requirement for activation of the alternative pathway is the presence of C3b, which is generated continuously in small amounts. C3b reacts with factors B and D to generate an enzyme (C3bBb) that cleaves C3 into C3a and C3b. The newly generated C3b interacts with additional factors B and D to form more C3bBb. The C3bBb enzyme dissociates rapidly unless it binds to properdin (P). Forming the complex C3bBbP stabilizes it.
Membrane Attack Complex
Formation of the membrane attack complex begins with enzymatic cleavage of C5. C5 binds to C3b for cleavage by the C5 convertase enzyme (the trimolecular complex C4b2b3b for the classic pathway and C3bBbP for the alternative pathway). Subsequent formation of the membrane attack complex is nonenzymatic and follows successive binding of C6 and C7 and C5b to form the C5b67 complex. C8 and C9 then bind sequentially to this complex, resulting in formation of the lytic plug.
Breakdown products of this cascade (anaphylotoxins C3a and C5a) stimulate chemotaxis of neutrophils and degranulation of basophils and mast cells. The anaphylotoxins have a powerful effect on blood vessel walls, causing contraction of smooth muscle and an increase in vascular permeability, probably mediated indirectly by release of histamine from mast cells. Bound C3 and C4 fragments act as opsonins to enhance phagocytosis and stimulate exocytosis from neutrophils, monocytes, and macrophages of granules that contain powerful proteolytic enzymes and free radicals. A link between complement activation and adaptive immunity is becoming recognized.
PHAGOCYTIC CELLS
Both polymorphonuclear leukocytes and monocytes phagocytize microorganisms during inflammatory reactions. Although monocytes show greater diversity in function and response, both types of cells recognize and ingest particles and soluble ligands through receptors on their cell surfaces and digest them in their lysosomes. They also have a number of oxygen-independent mechanisms that include lactoferrin, lysozyme, major basic protein, and defensins. Defensins are antimicrobial cationic peptides that are divided into a and b subfamilies. The a defensins are produced by neutrophils; epithelial cells produce the b defensins. The a defensins play a role in inflammation, wound repair, and specific responses. They increase bacterial adherence and induce histamine release. In contrast, b defensins regulate complement and inhibit proteases (13).
Monocytes
Monocytes originate in the bone marrow from pluripotential stem cells and are released into the blood. Tissue macrophages arise by maturation of monocytes that have migrated from the blood. In proliferation of immature macrophages, mitogens such as colony-stimulating factor (CSF), which is produced by fibroblasts, lymphocytes, and monocytes, play an important role. During inflammation, both of these processes increase dramatically. Giant cells arise either by fusion of macrophages or by failure of cytokinesis during mitosis. The most important functional property of the macrophage is its ability to recognize and ingest foreign and damaged materials. The capability of macrophages to recognize opsonized particles resides in their receptors, which bind the Fc portion of immunoglobulins and the C3 components of complement. Macrophages possess surface MHC molecules and have receptors for activation by lymphokines and for CSF, which regulates their function and proliferation. Monocytes also produce complement components, prostaglandins, interferons, proteases, and cytokines. Langerhans cells, another type of APC, are interspersed in the epithelial layer of the nasal mucosa and skin and help to induce T-cell responses. They present antigen to T cells.
During phagocytosis, particles bound to specific or nonspecific membrane receptors are surrounded by the cell membrane to form phagocytic vesicles. Endocytic vacuoles become secondary lysosomes after fusion with primary lysosomes. Within the lysosomal compartment, the contents are digested at acid pH by more than 40 hydrolytic enzymes. After ingestion of particles, macrophages and neutrophils undergo a respiratory burst. The burst is observed as a dramatic increase in consumption of oxygen and activation of membrane-associated oxidase. This oxidase reduces molecular oxygen to superoxide anion, which undergoes dismutation to hydrogen peroxide. Superoxide and hydrogen peroxide interact to give rise to hydroxyl radicals and singlet oxygen. These reactive metabolites of oxygen exert antimicrobial and antitumor effects.
Another group of effector molecules synthesized by macrophages includes nitric oxide and reactive nitrogen intermediates. The macrophage itself is protected from these oxygen metabolites by glutathione peroxidase and catalase. Many soluble agents, including antigen-antibody complexes, C5a, ionophores, and tumor promoters, can trigger the respiratory burst without phagocytosis.
Substances chemotactic for macrophages include C5a anaphylatoxin, bacterial products such as N-formylmethionyl peptides, and products from stimulated B and T lymphocytes. Also important are substances that inhibit migration away from sites of inflammation: lymphokines (macrophage inhibitory factor and macrophage activation factor) and proteolytic enzymes produced during activation of complement (factor Bb).
Macrophages are important in the initiation and regulation of the immune response. Macrophages that produce IL-12 increase bronchial responsiveness associated with eosinophil migration. Macrophages that produce IL-1 stimulate T-cell function, and they present immune molecules to lymphocytes. This function requires display of the same MHC determinants by both T cells and macrophages. The presence of IL-1 increases production of prostaglandins and leukotrienes, which can alter vascular permeability and bronchial tone. Interleukin-1 also induces production of acute-phase proteins, including complement components, fibrinogen, and clotting factors, and increases the activity of adhesion proteins such as ICAM-1.
Granulocytes
Polymorphonuclear leukocytes (neutrophils) accumulate at sites of acute inflammation. This requires a series of coordinated steps that include adherence to endothelium, extravascular migration, chemotaxis, membrane recognition and attachment to particles, phagocytosis, fusion of lysosomes and degranulation, and a burst of oxidative metabolism. Some of the genes responsible for the oxidative burst have been identified and associated with chronic granulomatous disease. A genetic locus on chromosome 1q42-q44 has been identified in patients with Chédiak-Higashi syndrome, a disease characterized by giant granules in neutrophils.
Blood neutrophils are composed of two interchangeable subpools: the circulating pool and the marginal pool. One of the early events in acute inflammation is an increase in neutrophil margination and adherence to the vascular endothelium. C5a, a component of complement, mediates neutrophil chemotaxis, although other chemoattractants from bacteria, stimulated leukocytes, products of coagulation or fibrinolysis, and oxidized lipids exist. The chemokines plus selectins assist with neutrophil adhesion to vascular endothelium. Neutrophils recognize particles by opsonins attached to them. These opsonins include immunoglobulins to which the neutrophil exhibits Fc receptors and the C3b fragment of complement. After phagocytosis, the processes described for mononuclear phagocytex applies to the neutrophil.
Eosinophils are produced in the bone marrow, circulate in the blood, and reside predominantly in tissues. Eosinophils have receptors for several cytokines and for IgG and IgE. They possess several adhesion molecules (ligands), which assist in chemotaxis. Their function is attributed to elaboration of a variety of cytokines, proteins, peroxidases, and enzymes. One of these, major basic protein, is cytotoxic and helminthotoxic. Also elaborated are eosinophil peroxidase, eosinophil-derived neurotoxin, Charcot-Leyden crystal protein, and eosinophil cationic protein. Survival of eosinophils in tissues is based on their need for several growth factors, such as IL-5, IL-3, and GM-CSF. In the absence of growth factors, eosinophils undergo programmed cell death or apoptosis.
Basophils are granulocytes that possess high-affinity IgE receptors. They contain histamine and other mediators, including cytokines. Basophils are believed to contribute to anaphylaxis by releasing histamine and are known to ontribute to allergic reactions at tissue sites, such as the nose, lungs, and skin.
IMMUNE SENESCENCE
With life expectancy increasing, investigations into the effects of aging on the immune system have increased. Results of unavoidable exposure to a large number of potential antigens (viruses, bacteria, foods, and self-molecules) influence the immune response. Changes reported with aging include (a) dysregulation of peripheral B and T cells with production of large clones, (b) alterations in lymphocyte subset distribution, signaling, and cytokine production, (c) thymic involution with a decreased output of T cells, (d) a void of virgin T cells to respond to new infectious and noninfectious disease, (e) an increase in the percentage of NK cells with a mature phenotype and associated impairment of their cytotoxic capacity and their response to IL-2, (f) decreased phagocytic capability of neutrophils, and (g) an increase in cell adhesion molecules. Low numbers of NK cell among elderly persons is associated with mortality and the risk of severe infection. Innate immunity, mediated by genes that remain in the germline configuration and encode for proteins that recognize conserved structures on microorganisms, is a much more ancient system of host defense. Innate immunity (chemotaxis, phagocytosis, defensins, and complement) is conserved with aging (14).
IMMUNOPATHOLOGY
Immunopathology is the study of an adaptive immune response that occurs in an exaggerated or inappropriate form and causes tissue damage. The response also has been called hypersensitivity, and it manifests itself only after a second contact with a particular antigen. Autoimmunity involves formation of IgG and IgM antibodies to self and reflects a deviation from the principle of self-nonself discrimination. There are autoantibodies to essentially every organ in the body. Several mechanisms may explain the presence of autoantibodies. For example, a foreign antigen can cross-react with a normal body structure, as in cross-reaction of specific streptococci and heart antigens in rheumatic heart disease. In other cases, the release of a previously sequestered self-antigen appears, as in postmumps orchitis. Still other cases involve a deficiency of suppressor T cells. Autoimmune mechanisms occur in myasthenia gravis, autoimmune hemolytic anemia, pernicious anemia, and Goodpasture syndrome.
Antibody (IgG and IgM) and antigen form soluble complexes that precipitate in basement membranes of blood vessels with considerable outflow of plasma. These vessels include those lining serosal surfaces, such as the peritoneum and pleura, joints, kidneys, and skin. The complexes activate complement and set in motion an inflammatory response characterized primarily by the influx of neutrophils. The inflammation harms the blood vessel walls and adjacent tissues.
Delayed-type hypersensitivity is the pathologic variant of normal T-cell-mediated immune response. Often the T-cell response to an environmental antigen can be overly enthusiastic. Much of the damage to the lung in tuberculosis is caused not directly by Mycobacterium tuberculosis but by the macrophages attracted by T-cell-derived cytokines. The macrophages specialize in destroying ingested material but are not adept at differentiating foreign antigens from host antigens. Adjacent tissues can be damaged as innocent bystanders. Delayed-type hypersensitivity also occurs in graft rejection and allergic contact dermatitis.
ALLERGY
Pollens and other potential allergens are deposited on the mucosal surface (Fig. 8.3). Antigens extracted from the pollens penetrate through or between epithelial cells and interact with APCs spread throughout the mucosa. Initial stimulation of the IgE mucosal immune response usually occurs in the tonsils and adenoids. Chronic exposure to low doses of antigen favors IgE over IgG production.
Production of IgE by B cells involves APCs and TH cells. Locally produced IgE first attaches to local mast cells. Excess IgE enters the circulation and binds to receptors on both circulating basophils and tissue-fixed mast cells throughout the body. Although the serum half-life of IgE is only 2½ days, mast cells may remain sensitized for many weeks after passive sensitization with atopic serum containing IgE.
Persons with a family history of asthma, eczema, hay fever, and urticaria and a positive skin test result are referred to as atopic. About 20% of the U.S. population have positive immediate wheal and flare skin reactions to common inhalant allergens. Parents with allergies have a higher than usual proportion of children with allergies—50% of children with two parents with allergies have an allergy. When only one parent has an allergy, the chance is about 30%. A family history of allergy is an important risk factor for allergic disease.
The incidence of allergic rhinitis is increasing in many industrialized nations. There is no obvious cause of this increasing occurrence. Pollution with diesel exhaust fumes and the prevalence of new antigens do not account entirely for this increase. The possible reduction of infection could be shifting T-helper responses from TH1 to TH2 cells (Fig. 8.4). Immunostimulatory DNA sequences that favor a TH1 response have been proposed as a means of immunotherapy to shift the allergic TH2 response toward a TH1 response.
The total amount of IgE alone is not predictive of an allergic state because genetic and environmental factors, such as parasitic infestation, affect the levels. The mode of inheritance of high levels of total IgE is not yet known, but many of the cytokines that control its regulation map to chromosome 5. Specific antigen-specific IgE responses frequently are associated with particular human leukocyte antigen (HLA) markers.
Mast cells are important in the allergic reaction. Mast cells are subtyped according to content of proteases. Both subtypes contain histamine and exist in the nasal mucosa. The final phenotype depends on local microenvironmental factors. The number of mast cells increases in the nasal mucosa after seasonal exposure to allergens. Evidence suggests that some microorganisms interact directly with mast cells and activate them to elicit an inflammatory response that clears bacteria—a possible link between mast cells and innate immunity.
Immunoglobulin E binds through its Fc receptor on the cell surface of mast cells. Cross-linking of IgE on the surface triggers degranulation. Activation of mast cells causes an influx of calcium ions. This process causes, first, exocytosis of granule content with the release of preformed mediators, such as histamine, heparin, and proteolytic enzymes (tryptase and b-glucosaminidase). Second, mast cell activation induces the synthesis of newly formed mediators from membrane-bound phospholipids. This results in production of prostaglandins, leukotrienes, and platelet-activating factor. Cytokines such as IL-3, IL-4, TNF2, and GM-CSFE also are produced by mast cells.
Minutes after antigen exposure, increases are detected in the levels of mast cell–associated mediators. Concurrent with the release of inflammatory mediators in nasal secretions, sneezing, rhinorrhea, nasal itching, and congestion begin. Localized changes around mast cells are amplified by neuronal reflexes. For example, stimulation of one side of the nasal cavity with antigen causes local histamine release, which stimulates sensory nerves. The sensory information travels to the central nervous system and stimulates parasympathetic signals that cause bilateral nasal secretion. The nervous system also potentially influences the reaction through release of neuropeptides.
The early response of mast cell degranulation does not entirely explain the symptoms of patients with allergic rhinitis. The following observations support this notion: (a) The duration of the early reaction to antigen is measured in minutes, whereas clinical disease is more prolonged, patients reporting nasal symptoms hours after pollen exposure. (b) Systemic glucocorticoids, although useful in refractory cases of allergic rhinitis, do not inhibit the early reaction. (c) Biopsy of the nasal mucosa during the allergy season shows inflammatory cellular infiltration, whereas study of the early reaction shows only mast cell degranulation and tissue edema. (d) The dose of pollen necessary to induce symptoms during experimental provocation exceeds severalfold the amount needed to produce a response during the allergy season. (e) Changes in reactivity to nonspecific irritants occur during seasonal exposure but not during the early response. Allergic rhinitis therefore cannot be strictly considered an immediate hypersensitivity reaction. The concept of the pathophysiologic mechanism of allergic rhinitis must be expanded.
The late response is defined as recurrence of symptoms and the appearance of mediators in nasal secretions hours after antigen exposure. Depending on the variable analyzed, the incidence of late reactions varies from 16% to 53% among patients with allergies with an onset within 3 to 11 hours after antigen challenge. Among these patients, the symptoms recur spontaneously in concordance with an increase in the levels of some but not all of the same mediators of the early reaction.
Hours after the early response, a marked overall increase occurs in the number of cells recovered in lavage of collected nasal secretions and in biopsy specimens obtained from the nasal mucosa. The increase is specific for persons with allergies and is easily detected for about two thirds of persons with allergies. The influx of eosinophils, neutrophils, and lymphocytes is maximal 4 to 11 hours after exposure to antigen and is mediated by adhesion molecules on the endothelium (ICAM-1, VCAM-1, selectins, and integrins) and by their counterligands on the cells (VLA-1, LFA-1, macrophage-1 antigen [Mac-10], and platelet-endothelial cell adhesion molecule 1 [PECAM-1]) (15) (Fig. 8.5). There appears to be a greater eosinophil influx among persons with late reactions. The nasal mucosa and surface secretions show similar but not identical changes. For example, the mucosa contains greater numbers of TH2 lymphocytes.

In addition to their function as a barrier, cells in the epithelium are involved in the immune process. Epithelial cells secrete IL-6, IL-8, and GM-CSF. Langerhans cells are interdigitated with epithelial cells and present antigens to and induce activation and differentiation of T cells. Intraepithelial lymphocytes are predominantly T cells and play a role in the immune response. These cells secrete IL-2, IL-5, IFN-t, and transforming growth factor b and have cytotoxic functions (16).
Rechallenge with allergen 11 hours after the initial provocation increases the amount of inflammatory mediators in a pattern suggestive of both mast cell and basophil activation. More important, the dose of antigen necessary to induce a clinical reaction is markedly reduced. Oral glucocorticoids inhibit this increased reactivity as well as the late reaction and the cellular influx, supporting the importance of this reaction. Repeated exposure to antigen can maintain a constant inflammatory process in the nasal mucosa. Progressively smaller doses of antigen induce the same allergic response (priming), explaining the persistence of strong symptoms even beyond the peak of the pollen season. With perennial antigens, this phenomenon can be constant, and patients have symptoms all year.
There also is an increase in nonspecific nasal airway reactivity to histamine, methacholine, and cold, dry air after antigen exposure. Such reactivity correlates with an increase in the number of eosinophils and with an increase in vascular permeability in the nasal mucosa. This increase in nonspecific nasal reactivity probably is related to the inflammatory cellular infiltration that occurs after antigen stimulation. Topical steroids have been shown not only to inhibit the early and late responses to antigen but also to inhibit the nonspecific reactivity due to antigen and the accompanying eosinophil influx, even when given after challenge.

NEUROLOGY

2009-02-07T06:25:00.000-10:00

The diagnosis and management of the numerous and complex neurologic conditions that present in the head and neck are predicated on an understanding of the neuroanatomic and neurophysiologic characteristics of this region (1,2,3 and 4) (Fig. 9.1, Fig. 9.2, Fig. 9.3, Fig. 9.4, Fig. 9.5, Fig. 9.6 and Fig. 9.7), particularly of the cranial nerves (Table 9.1). Many neurologic diseases have manifestations in the head and neck. In diseases such as cerebrovascular accidents and tumors, the location of the lesion determines the manifestations of the disorder. Demyelinating or degenerative diseases also manifest ear, nose, and throat symptoms.
NEUROMUSCULAR DISORDERS
Multiple Sclerosis
Multiple sclerosis is an inflammatory disease involving areas of demyelinization in the central nervous system. This disease primarily affects young adults and is characterized by exacerbations and remissions. The geographic distribution is distinct: the incidence is higher in the higher latitudes and almost nil at the equator. Vertigo is the presenting problem among 7% to 10% of patients and may eventually occur among as many as 30% of patients. Nystagmus occurs among 70% of patients. This is usually horizontal nystagmus, although 33% of patients with nystagmus have vertical nystagmus. Diplopia often is caused by involvement of extraocular muscles from lesions in the medial longitudinal fasciculus, which links the nuclei of cranial nerves VI and III and subserves conjugate lateral gaze. Bilateral internuclear ophthalmoplegia due to a lesion of the medial longitudinal fasciculus strongly indicates the existence of multiple sclerosis. Deafness is rare in multiple sclerosis. The Charcot triad in multiple sclerosis consists of nystagmus, scanning speech, and intention tremor (5). Multiple sclerosis can be diagnosed reliably with appropriate diagnostic studies. The following findings establish the diagnosis: magnetic resonance images that show small, demyelinated foci in the white matter; abnormal brainstem auditory or visual evoked responses, and elevated protein level in the cerebrospinal fluid with the presence of oligoclonal immunoglobulin banding.
Myasthenia Gravis
Myasthenia gravis is caused by impaired transmission across the myoneural junction due to the presence of antibodies to the acetylcholine receptor. Onset occurs at all ages with clustering among young women and older men. This disease is characterized by weakness and abnormal fatigue of striated muscles. Remission and exacerbation are characteristic. Ocular muscles are involved in more than 90% of these patients. There often is weakness of facial, laryngeal, and pharyngeal muscles. The cricopharyngeal muscle often is involved. The weakness is greater after exercise or at the end of the day. Nystagmus and vertigo are rare. Transient neonatal myasthenia gravis occurs among one in seven newborns born to a mother with myasthenia gravis. The infants are unable to suck and swallow. Diagnosis is made from the history and the findings of relief of weakness after administration of neostigmine (6). Myasthenia gravis is associated with thymoma among 10% of patients. The disease is autoimmune in nature and mediated by circulating immunoglobulin G antibodies to the acetylcholine receptor. A positive result for the presence of antiacetylcholine receptor antibody (present in approximately 85% of patients), a positive result of an edrophonium test, and abnormal results of repetitive stimulation electromyography are highly reliable in establishing the diagnosis.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motor neurons of the central nervous system. The disease is characterized by progressive muscular weakness and atrophy along with spasticity. The otolaryngologic manifestations are dysphagia, fasciculation, atrophy of the tongue, dysarthria, and pseudobulbar palsy. Deep tendon reflexes are hyperactive. This disease usually occurs among middle-aged and older persons, mainly men (7).
Syringobulbia
Syringobulbia is a progressive, degenerative disease that involves cavitation of central parts of the cervical spinal cord (syringomyelia). It extends superiorly into the medulla oblongata and pons and into the area of the descending tract of the trigeminal nerve or other nuclei of bulbar structures. Signs are analgesia and thermoanesthesia of the face, atrophy and weakness of the tongue, palatal paralysis, and vocal cord paralysis. There is usually shoulder and upper extremity involvement (6). Arnold-Chiari type I malformation is frequently associated. This malformation by itself even without syrinx formation can cause Menière-like auditory and vestibular symptoms (8).
Poliomyelitis
Poliomyelitis is a viral illness usually affecting children. It has been almost eliminated in the United States through vaccination. When poliomyelitis does occur, there usually are several cases in a community. The onset of disease is acute and is characterized by fever, muscle weakness, tight neck muscles, decreased deep tendon reflexes, and dysphagia (7). Examination of the cerebrospinal fluid shows acute meningitis.
Guillain-Barré Syndrome
In Guillain-Barré syndrome, an acute postinfectious inflammatory polyneuropathy, the patient has ascending limb weakness and muscle tenderness that in rare instances progresses to dysphagia, respiratory failure, and minimal sensory symptoms. The patient continues to have a fever. Guillain-Barré syndrome usually follows a viral illness or inoculation with vaccine. The Miller-Fisher variant of Guillain-Barré syndrome begins with weakness of facial and neck muscles before limb weakness develops (9). The diagnosis usually is confirmed when there is an elevated level of protein in the cerebrospinal fluid without a cellular response.
Tetanus
Tetanus is caused by a toxin produced by clostridia, usually from infection of puncture wounds or pressure ulcers. The disease is characterized by trismus, rigid abdominal muscles, dysphagia, and perspiration. External stimuli may trigger muscle spasms and even convulsions. Laryngeal spasm may occur. Tetanus can be confined to the head and neck. There usually is a history of injury, but often the trauma was trivial or not reported (10). Tetanus often occurs among elderly persons who have not maintained their immunizations.
Dystonia
Dystonia of the tongue or lips and facial grimacing may be caused by extrapyramidal disease or drug intoxication. Torsion spasm involves excess muscle tone in large muscle groups. This may involve the entire body. Movements are slow, undulant, writhing, and twisting. This disorder may involve only the face, tongue, head, and neck, leading to dysarthria, facial grimacing, and torticollis. Meige syndrome, known as cranial dystonia, presents with focal or segmental dystonia involving the cranial muscles. The most common example is blepharospasm (11). Dystonia musculorum deformans is a rare, progressive, familial disorder manifesting dystonia. Tardive dyskinesia is a dystonia of the lips, tongue, and facial muscles. This is a late side effect of phenothiazines that can occur even after discontinuation of the drug. Spasmodic torticollis involves dystonic movement of the head, neck, and shoulders. Initially, this is intermittent, but it can later develop into persistent muscle contraction with deviation of the head. This condition can be congenital or acquired. Some cases may be psychogenic (6). Spastic dysphonia is considered to be a focal dystonia of the larynx.
Palatal Myoclonus
Palatal myoclonus involves involuntary movement of the pharynx and soft palate. This movement can be suppressed by voluntary effort. Palatal myoclonus is caused by lesions of the olivodentatorubromesencephalic pathway (6).
CEREBROVASCULAR ACCIDENT
Cerebrovascular accidents (CVAs) can be caused by hemorrhage, thrombosis, or emboli.
Hemorrhage
Hemorrhage tends to occur suddenly and during activity, especially among persons with hypertension. Hemorrhage is the most common form of CVA in middle age. Thrombosis is the most common form of CVA. It tends to occur among older patients, often during rest. Thrombosis may be preceded by transient neurologic involvement referred to as transient ischemic attacks. Thrombosis often begins with an intermittent or gradual course. Dural sinus thrombosis occurs most commonly in childhood (3 to 5 years). The longitudinal and straight sinuses are most frequently involved. Among adults, thrombosis often complicates a debilitating disease, hydration, or prolonged labor and delivery. Dural sinus thrombosis may be associated with infection of the ears and paranasal sinuses. Signs of dural sinus thrombosis are edema of the forehead, distention of scalp veins, lower limb spasticity, seizures, and hemiplegia. Persistent convulsions and sudden loss of consciousness are common.
Embolism
Embolism often is sudden in onset, accounts for about one third of CVAs, and is the most likely form of CVA to resolve. Among 10% of patients who have strokes, atheromatous plaques are found in the proximal arterial system (carotid or vertebral basilar arteries). Atrial fibrillation or flutter and paradoxical emboli are recognized cardiovascular contributing factors. Embolism among younger patients often is associated with valvulitis or acute infection of the throat or teeth. The history includes fever, malaise, weight loss, and joint pain. There often is a sudden onset of lethargy or coma and a cardiac murmur. Petechiae and hematuria may exist.
Subarachnoid Hemorrhage
Subarachnoid hemorrhage usually is caused by rupture of an aneurysm. This is the most common form of CVA among patients between the ages of 17 and 35 years. Signs of subarachnoid hemorrhage are rigidity of the neck, severe nuchal pain, and impairment of consciousness.
Transient Ischemic Attacks
Narrowing of the internal carotid artery or middle cerebral artery can be associated with contralateral transient muscle weakness or sensory disturbances referred to as transient ischemic attacks. If the left or dominant hemisphere is involved, there may be a speech disturbance. Intermittent blindness can occur in the ipsilateral eye (amaurosis fugax). If the internal carotid artery is involved, a bruit may be heard in the neck.
Posterior Inferior Cerebellar Artery Thrombosis
Posterior inferior cerebellar artery thrombosis (Wallenberg syndrome) is characterized by vertigo, dysphagia, ipsilateral facial paresthesia and hypesthesia, ipsilateral Horner syndrome, and ipsilateral incoordination. There may be hypalgesia of the contralateral trunk and limbs along with ipsilateral hypesthesia.
Basilar Artery Insufficiency
Basilar artery insufficiency is associated with recurrent vertigo, transient decrease in vision, dysphagia, dysarthria, and diplopia. There may be hemiparesis, which may shift from side to side. The patient may have episodes of confusion or loss of consciousness.
Thrombosis of the Anterior Spinal Artery
Thrombosis of the anterior spinal artery affects the pyramids and emerging hypoglossal fibers. It is associated with hemianesthetic hemiplegia or with hypoglossal hemiplegia. There is a contralateral loss of proprioception and a decrease in tactile sensation. This may spare the hypoglossal nerve. Another result of anterior spinal artery thrombosis is hemiplegia cruciata, a lesion of the decussation of the pyramid. The patient has contralateral and ipsilateral spastic paresis of the lower extremities, may have ipsilateral flaccid paresis and atrophy of the sternocleidomastoid and trapezius muscles, and may have ipsilateral paresis of the tongue.
Anterior Inferior Cerebellar Artery Thrombosis
Anterior inferior cerebellar artery thrombosis involves the tegmentum of the upper medulla, lower pons, restiform body, the lower part of the cerebellar peduncle, and the inferior surface of the cerebellar peduncle. The deficits include ipsilateral loss of facial pain, light touch and temperature sensations, ipsilateral Horner syndrome, ipsilateral deafness, vertigo, and ipsilateral facial palsy. The patient has ipsilateral cerebellar ataxia and a contralateral decrease in pain and temperature sensation in the limbs and trunk. This lesion may follow excision of acoustic neuroma.
Superior Cerebellar Artery Thrombosis
Superior cerebellar artery thrombosis causes choreiform or choreoathetoid involuntary movement and contralateral loss of pain and temperature sensation in the face and body. The patient has ipsilateral cerebellar ataxia with hypotonia, nausea and vomiting, and slurred speech. There may be a central facial palsy, ipsilateral Horner syndrome, and partial deafness. This lesion involves the lateral tegmentum of the pons and midbrain, superior cerebellar peduncle, superior surface of the cerebellum, and cerebellar peduncle.
Thrombosis of the Vertebral Artery
Thrombosis of the vertebral artery (Avellis syndrome) involves the spinothalamic tract, nucleus ambiguus, and usually the bulbar nucleus of the accessory nerve. The patient has ipsilateral paralysis of the soft palate and larynx, ipsilateral anesthesia of the pharynx and larynx, and ipsilateral loss of taste. There is contralateral loss of pain and temperature sensation in the trunk and extremities. Ipsilateral Horner syndrome occasionally results.
Cestan-Chenais Syndrome
Cestan-Chenais syndrome is occlusion of the vertebral artery inferior to the origin of the posteroinferior cerebellar artery. This lesion involves the nucleus ambiguus, restiform body, and descending sympathetic pathways. The syndrome is characterized by paralysis of the soft palate, pharynx, and larynx, Horner syndrome, and ipsilateral cerebellar ataxia, contralateral hemiplegia, and decreased proprioception and tactile sensation. Possible involvement of cranial nerves XI and XII may cause ipsilateral paralysis of the sternocleidomastoid and trapezius muscles and the tongue. The descending tract of the trigeminal nerve may be involved. The result is ipsilateral loss of temperature and pain sensation in the face.
Babinski-Nageotte Syndrome
Babinski-Nageotte syndrome involves scattered lesions in the distribution of the vertebral artery. This causes ipsilateral paralysis of the soft palate, larynx, pharynx, and tongue, ipsilateral decrease in taste sensation on the posterior third of the tongue, diminished pain and temperature sensation on the face, and Horner syndrome. There is a contralateral spastic hemiplegia and loss of proprioception and touch. There may be decreased pain and temperature sensation in the trunk and limbs.
Basilar Artery Thrombosis
Basilar artery thrombosis causes a disorder in superficial and deep sensation in the extremities, trunk, and sometimes the face. The pupils usually are miotic. The patient usually has decerebrate rigidity, profound coma, and respiratory and circulatory difficulties. This can affect bilateral cranial nerves and long tracts. There is bilateral supranuclear fiber involvement to the bulbar nuclei.
Thrombosis of the Medial Pontine Branches
Thrombosis of the medial pontine branches involves the nuclei of cranial nerves VI and VII, the medial longitudinal fasciculus, medial lemniscus, and pyramidal tract. The patient has ipsilateral facial paralysis and paralysis of the lateral rectus muscle or of lateral conjugate gaze. There is a contralateral lateral hemiplegia, loss of proprioception, and decrease in sensation of light touch.
Thrombosis of Lateral Pontine Branches
Thrombosis of lateral pontine branches involves the middle cerebellar peduncle, the superior olivary body, the facial nucleus, the vestibular and cochlear nuclei, and a portion of the motor and sensory nuclei of the trigeminal nerve. The deficit involves ipsilateral cranial nerves V, VII, and VIII and ipsilateral cerebellar ataxia. The patient frequently has contralateral diminution of pain, temperature, proprioception, and tactile sensation on the trunk and limbs.
Thrombosis of the Upper Pontine Branches
Thrombosis of the upper pontine branches of the basilar artery affects the pyramidal tract, medial lemniscus, spinothalamic tract, and the ventral and dorsal secondary ascending tract of the trigeminal nerve. This causes contralateral hemiplegia that includes the face and tongue. There is also a loss of proprioception, pain, and temperature sensation of the face, extremities, and trunk.
Thrombosis of the Internal Auditory Artery
Thrombosis of the internal auditory artery causes ipsilateral deafness and loss of vestibular function.
Jackson Vagus-Accessory-Hypoglossal Paralysis
Jackson vagus-accessory-hypoglossal paralysis is a nuclear or radicular lesion of cranial nerves X, XI, and XII. The patient has ipsilateral flaccid paralysis of the soft palate, pharynx, and larynx. Flaccid weakness and atrophy of the sternocleidomastoid and trapezius muscles and the tongue also occurs.
Vagus-Accessory Syndrome
Schmidt (vagus-accessory) syndrome is a lesion of the nucleus ambiguus and the bulbar and spinal nuclei of cranial nerve XI. It results in ipsilateral paralysis of the soft palate, pharynx, and larynx and in flaccid weakness and atrophy of the sternocleidomastoid and trapezius muscles. Ipsilateral paralysis of the soft palate, pharynx, and larynx and paralysis and atrophy of the tongue are caused by Tapia syndrome (vagohypoglossal syndrome), a tegmental lesion in the lower third of the medulla that involves the nucleus ambiguus and the hypoglossal nerve.
Vernet Syndrome
Vernet syndrome, a lesion at the jugular foramen, can be a result of a vascular lesion, a tumor, aneurysm of the internal carotid artery, thrombosis of the jugular bulb, tuberculosis, or syphilis. The most common cause, however, is basilar skull fracture, which produces ipsilateral paralysis of cranial nerves IX, X, and XI. Villaret syndrome is a lesion of the retropharyngeal or retroparotid space that causes ipsilateral paralysis of cranial nerves IX, X, and XI and of cervical sympathetic fibers, producing Horner syndrome.
Collet-Sicard Syndrome
Collet-Sicard syndrome is similar to Villaret syndrome, but there is no Horner syndrome. Glossolaryngoscapulopharyngeal hemiplegia is caused by a complete lesion of cranial nerves IX through XII.
Garel-Gignoix Syndrome
Garel-Gignoix syndrome involves the vagus and accessory nerves below the jugular foramen (9,10).
TUMOR
Otolaryngologic symptoms can be caused by tumor involvement of nerves of the head and neck region.
Glioma
Two percent of gliomas among children are pinealoma. The patient has extraocular muscle involvement, ptosis, restriction of upward gaze, and bilateral hyperacusis. Some patients have sexual changes and macrogenitosomia praecox. Central nervous system tumors among adults usually are supratentorial.
Meningioma
Meningioma constitutes 15% of intracranial tumors. These usually slow-growing tumors originate in the sagittal sinus, the sphenoid ridge, or the olfactory groove. If the tumor arises on the sphenoid ridge, there may be unilateral exophthalmos and oculomotor nerve involvement with subsequent diplopia and vision loss. Signs of olfactory groove involvement are unilateral or bilateral anosmia and mental or personality changes. There may be optic atrophy late in the course.
Kennedy Syndrome
Kennedy syndrome is associated with a tumor in the olfactory groove. Findings are optic atrophy on the side of the tumor and papilledema on the opposite side.
Acoustic Neuroma
Acoustic neuroma originates along the vestibular nerve. Two percent of intracranial tumors are acoustic neuroma. Vertigo with or without tinnitus usually is the first symptom, and recurrent episodes presumed to be benign can occur. The patient later has hearing loss, ipsilateral corneal hypesthesia, and incoordination of cerebellar origin. Late in the course of acoustic neuroma, ipsilateral facial paresis develops. Because the tumors are most frequently on the vestibular portion of cranial nerve VIII, canal paresis with caloric testing is an early finding.
Nasopharyngeal Carcinoma
Nasopharyngeal carcinoma can include extension of central nervous system tumors into the nasopharynx and sinuses. Tumors in this region can impair hearing. Extension of nasopharyngeal tumors can cause Garcin syndrome, which is paralysis of cranial nerves III through X. The effects usually are unilateral but can be bilateral. This condition is caused by lesions in the retropharyngeal space, usually produced by infection in this area but also caused by granuloma or metastasis or extension from the nasopharynx.
Epidermoid Tumor
Epidermoid tumors are the third most common primary mass lesion of the cerebellopontine angle. The patient may have multiple cranial nerve palsies with or without brainstem involvement. Hearing loss generally appears late in the course of the tumor.
Metastatic Tumor
Metastatic tumors tend to have a rapid course, and evidence of neoplasia elsewhere usually can be obtained. Multiple upper and lower cranial nerve palsies usually evolve. Glioma from the brainstem or cerebellum also can invade the cerebellopontine angle, producing symptoms of a cerebellopontine angle mass lesion. Aneurysms also may appear in the cerebellopontine angle.
Tumor of the Glomus Jugulare
Tumor of the glomus jugulare involves cranial nerves IX, X, and XI at the jugular foramen. There often is evidence of dysfunction of cranial nerves VII and VIII.
Pituitary Adenoma
Pituitary adenoma can be classified as functional (secreting) or nonfunctional (nonsecreting). Prolactinoma is the most common pituitary tumor and occurs most frequently among young women. Symptoms are galactorrhea with or without amenorrhea. Most patients respond to medical treatment with bromocriptine. Growth hormone adenoma causes gigantism among children before closure of the epiphyses of the long bones. Adults have acromegaly and enlargement of the jaw, hands, and feet. Other signs are hyperhidrosis, hypertrichosis, diabetes, cardiac disease, and paresthesia, such as carpal tunnel syndrome.
Corticotropin-secreting tumors manifest as Cushing disease, which is characterized by truncal obesity, moon facies, buffalo hump, pigmented stretch marks, hypertension, and hirsutism. The lesions usually manifest as microadenomas. Nelson syndrome, hyperpigmentation, and increasing sellar size can occur after bilateral adrenalectomy for corticotropin-secreting tumors. In these patients, the tumors are large and aggressive.
Nonfunctional pituitary tumors manifest as decreased hormonal function or without endocrine deficiencies. Patients often have panhypopituitarism with visual symptoms. The patient may have increased intracranial pressure or extraocular muscle palsy. The visual symptoms are caused by suprasellar extension of the adenoma, which affects the optic chiasm. This causes bitemporal hemianopia and progressive loss of visual acuity. Extraocular muscle palsy is caused by lateral extension of the tumor toward the cavernous sinus (6,9).
FACIAL PAIN
Sinusitis is a common cause of facial pain and headache. Trigeminal neuralgia, usually induced by palpation of a trigger zone, causes severe pain. Sphenopalatine neuralgia (Sluder syndrome) is localized facial pain associated with vasomotor abnormality, such as lacrimation, rhinorrhea, and salivation. The pain involves the eye, nose, palate, maxillary teeth, ear, and temple. Glossopharyngeal neuralgia involves unilateral throat pain associated with ipsilateral rhinorrhea, salivation, coughing, and facial burning. Postherpetic neuralgia is similar to trigeminal neuralgia. It occurs after attacks of herpes zoster. Trotter syndrome involves pain in the mandibular division of cranial nerve V, unilateral deafness, ipsilateral palate hypomotility, and trismus. Ramsay Hunt syndrome is caused by herpes zoster infection of the geniculate ganglion. Signs are vesicles on the ear, oral mucosa, tonsils, pharyngeal mucosa, and posterior third of the tongue; facial palsy; loss of taste; decreased salivation; palatal paralysis; and pain. Eagle syndrome is caused by elongation and calcification of the styloid process along with calcification of the stylohyoid ligament. Symptoms are parapharyngeal pain, dysphagia, odynophagia, trismus, headache, and facial pain. Vail syndrome, vidian nerve neuralgia, causes unilateral pain of the nose, eye, face, neck, and shoulder.
OTHER FACIAL SYNDROMES
Horner syndrome is caused by interruption of sympathetic pathways in the medulla, spinal cord, and sympathetic trunk. This syndrome is characterized by constriction of pupils, enophthalmos, ptosis, and decreased sweating of the ipsilateral face. The gustatory lacrimal reflex (crocodile tears) is ipsilateral tearing when spicy foods are placed on the tongue. This is caused by faulty regeneration of nerves responsible for salivation with those responsible for lacrimation. Frey syndrome (auriculotemporal syndrome) causes flushing, a sensation of heat, and excessive perspiration over the cheek and pinna after ingestion of spicy food. This is caused by misdirected regeneration of secretomotor fibers, often after injury to the auriculotemporal nerve (4).
COMPLICATIONS OF EAR AND SINUS INFECTION
Osteomyelitis
Osteomyelitis occurs through extension of infection from the paranasal and mastoid sinuses. This usually involves the temporal, frontal, and parietal bones. Facial nerve palsy and vertigo can be caused by osteomyelitis of the temporal bone. If it erupts into the epidural space, the infection causes an epidural abscess. The patient has fever, malaise, tenderness, and pain. Nuchal rigidity is rare.
Subdural Empyema
Extension of infection through the dura can cause subdural empyema. This disorder is characterized by localized headache and can mimic mastoid or sinus infection. The patient has fever, malaise, and decreased consciousness. Seizures, nuchal rigidity, and other neurologic deficits follow.
Meningitis
Meningitis is the most common intracranial infection. The pia mater and arachnoid are infected. Headache, lethargy, and irritability are early signs. Other signs of meningitis are nuchal rigidity, limited flexion of the legs, altered mental status, and fever. Diagnosis is made by means of analysis of cerebrospinal fluid, which shows pleocytosis (more than 1,000, mostly polymorphonuclear, leukocytes), elevated protein level, and decreased glucose level. Antibiotic therapy should be guided by the cerebrospinal fluid culture results.
Brain Abscess
Brain abscess forms by means of direct extension, hematogenous spread from septic thrombophlebitis, and extension through congenital defects, traumatic fistulae, or tumors. Brain abscess begins as localized cerebritis consisting of leukocytic infiltration and microscopic necrosis. At this stage, it is difficult to diagnose. In 7 to 10 days, a capsule forms, and the abscess enlarges and causes edema in adjacent tissues, producing neurologic symptoms. Between 40% and 50% of brain abscesses are of otogenic origin. Sinus infection accounts for about 10%. General symptoms are lethargy, headache, and fever. Focal signs depend on the location of the abscesses. Frontal lobe abscesses, almost exclusively the result of paranasal sinus infection, rarely have localizing symptoms. Increased intracranial pressure, stupor, and papilledema are signs of abscesses in this area. Brain abscesses can cause brainstem herniation and can rupture into the ventricular system.
Orbital Cellulitis
Extension of paranasal sinusitis into the orbit can cause orbital cellulitis, which causes chemosis, exophthalmos, diplopia, and immobility of the globe. Orbital cellulitis can advance to orbital abscess with ophthalmoplegia, proptosis, and visual loss. Optic neuritis characterized by acute loss of vision, decreased pupillary response, and pain with eye movement can be caused by extension of posterior ethmoidal or sphenoidal sinusitis. Fungal involvement with mucormycosis is a life-threatening infection associated with diabetes mellitus and immunosuppression.
Superior Orbital Fissure Syndrome
Superior orbital fissure syndrome usually is a complication of sphenoid sinusitis. The abducent nerve is paretic, and there may be involvement of cranial nerves III, IV, and V. The patient has diplopia, exophthalmos, ophthalmoplegia, and decreased sensation over the forehead.
Cavernous Sinus Thrombosis
Cavernous sinus thrombosis is the result of phlebitis spreading from the ethmoid and sphenoid sinuses. The eye becomes proptotic and chemotic, and the eyelid is edematous. Involvement of cranial nerves III, IV, and VI causes ophthalmoplegia (9).