TITLE: OTOLARYNGOLOGIC MANIFESTATIONS OF SYSTEMIC DISEASE
SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds
DATE: February 19, 1997
RESIDENT PHYSICIAN: James Grant, M.D.
FACULTY: Francis B. Quinn, Jr., M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.

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"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."

OTOLARYNGOLOGIC MANIFESTATIONS OF SYSTEMIC DISEASE

The otolaryngologist undoubtedly diagnoses and treats various head and neck manifestations of an underlying systemic disease. Indeed, pathology in this area may often be the initial marker for a larger disease process. It takes diligence and a high degree of suspicion for the physician to make the diagnosis. The systemic diseases may be a connective tissue disorder, granulomatous disease, hematological / oncological disease, nutritional disorder, metabolic disorder, neurological, or a systemic infectious disease.

CONNECTIVE TISSUE DISORDERS/GRANULOMATOUS DISEASES

Rheumatoid Arthritis

Characterized by an autoimmune induced inflammatory reaction to the peripheral synovial joints, it typically affects women more frequently than men in their fourth to fifth decade of life. Common signs and symptoms include subcutaneous rheumatoid nodules, morning stiffness, joint pain and swelling, and constitutional symptoms of malaise, fever, etc. Additionally, there may be more serious cardiac involvement (such as pericarditis, myocarditis, rheumatoid nodules in the myocardial tissue), cutaneous vasculitis, neurological disease (mononeuritis multiplex), and diffuse pulmonary manifestations (pleural effusion, pulmonary vasculititis).(1) Because of synovial joint involvement in this disease process, the head and neck pathology is a direct consequence. The joint spaces typically involved include the cricoarytenoid joint, the ossicular joints, the temporomandibular joint space, and the cervical spine joint. Rheumatoid involvement of the larynx is the most common, however, and may present as: Temporomandibular joint dysfunction may also be so severe that an anterior open bite deformity may exist. In addition, these patients may have otologic complaints of hearing loss either conductive secondary to synovitis of the ossicular joint or sensorineural from an autoimmune related disorder of the inner ear. Involvement of the cervical spine may result in disruption of the joint space with possible atlanto-occipital subluxation during neck hyperextension.(3)

Polymyositis / Dematomyositis

These disease entities are characterized by an inflammatory myopathy that clinically presents as weakness, tenderness, and progressive axial muscle wasting. The dermatomyositis variant has a distinct heliotrope rash which is seen on the face. For the otolaryngologists, these patients may complain of difficulty with phonation and deglutition secondary to involvement of the tongue muscle, while they may also have nasal regurgitation from palatal and pharyngeal muscle wasting. Dysphagia is also common as there is frequently dysfunction with the superior constrictors, cricopharyngeus, and esophageal muscles. Diagnosis of polymyositis / dermatomyositis is made by characteristic EMG findings, elevated creatinine phosphokinase levels, and finding proximal muscle weakness. Of note, there may be an underlying malignancy of the lung, prostate, ovary, uterus, or colon in approximately 10% of these patients presenting with this systemic disease.(4)

Relapsing Polychondritis

This is another example of a diffuse inflammatory disease with involvement of cartilaginous structures with progressive, gradual replacement with granulation and fibrous tissue. Typically affecting females, it generally occurs in the age range of 35 - 45. Systemically, it may affect any cartilage structure, but also may have severe cardiovascular involvement of aortitis, vasculitis, valvular insufficiency, and aneurysms in approximately 30% of the affected patients.(5) In the head and neck region, the cartilaginous structures of the ear and nose are commonly involved, with deformities related to tissue destruction (i.e. saddle nose). In auricular chondritis, the lobule is spared as is the external auditory canal; however, there is frequently a concomitant serous otitis media. There may also be laryngeo-trachaeal involvement with the possibility of later subglottic stenosis. It should be noted that in the adult patient with a clinical finding of subglottic stenosis without an identifiable cause, the physician should entertain the possibility of relapsing polychondritis, sarcoidosis, or Wegener's granulomatosis.(6) Resolution of the polychondritis may spontaneously resolve after a few days from the onset, otherwise anti-inflammatory medications are the mainstay for symptomatic relief. Surgical reconstruction of the nose or ear may later be indicated.

Sjogren's Syndrome

Classified into two subtypes, primary Sjogren’s syndrome is also referred to as the sicca complex (keratoconjunctivitis plus xerostomia), while secondary Sjogren’s syndrome is associated with another connective tissue, usually rheumatoid arthritis. This a chronic disease of immune mediated destruction of exocrine glands with resulting desiccation of the associated mucous membranes. There is a predisposition based on the major histocompatibility complex as approximately 90% of the females affected with primary Sjogren's are HLA B8 and HLA DR3. The clinical manifestations include severe gingivitis, dental caries, periodontal disease secondary to xerostomia, while corneal ulceration may be noted secondary to keratoconjunctivitis. There may also be generalized parotid swelling secondary to lymphocytic infiltration. In addition, there may tongue atrophy/glossitis and extensive nasal crusting with epistaxis from the dry mucous membranes. Systemic manifestations include gastric atrophy, pancreatic insufficiency, pericarditis, neuropathy, and pleuritis.(7) Of importance, these patients have 44 times relative risk of non-Hodgkin's lymphoma and should be considered especially in light of a patient with a rapidly enlarging parotid gland.(8) Diagnosis is based on finding xerostomia/xerophthalmia, associated connective tissue disease, and noted lymphocytic infiltration in a minor salivary gland biopsy.

Amyloidosis

This is rare disease that is marked by deposition of extracellular fibrillar protein in various tissues. There are several variants of this disease. There are two forms of systemic amyloidosis, primary and secondary. In primary systemic amyloidosis, the areas generally affected are the heart, tongue, and gastrointestinal tract, while in secondary systemic amyloidosis, there is an underlying chronic inflammatory disease such as tuberculosis, osteomyelitis, or rheumatoid arthritis and the tissues usually involved are the spleen, adrenals, liver, and kidneys. In the localized form of amyloidosis, the amyloid deposits are contained in a specific anatomical region, such as isolated tongue involvement. Finally, there is a systemic form of amyloidosis associated with multiple myeloma, where the tissues affected are the same as in primary systemic amyloidosis.(9) In the head and neck region, the tongue is the most site of amyloid deposition, with 12% of the patients having severe macroglossia. The larynx may also be involved with the ventricle being the most common followed by false vocal cords, aryepiglottic folds, and the subglottic region.(10) Diagnosis is based on microscopic exam of biopsied material showing green, bifringement particles under polarized light after staining with Congo red. Treatment is by excision of symptomatic deposits.

Cogan's Syndrome

This is a disease of young adults that presents after an otherwise unremarkable upper respiratory infection. While it may be linked to an autoimmune reaction to the organism Chlamydia trachomatis, its cause is uncertain. It has systemic manifestations of aortitis, aortic valve insufficiency, pleuritis, pericardial effusion, coronary arteritis, and possibly myocardial infarction. In the head and neck, it is seen as a nonsyphilitic interstitial keratitis and bilateral audiovestibular symptoms such as fluctuating hearing loss, vertigo, tinnitus, and aural fullness. In a small percentage of the patients, there may be progression to complete absence of vestibular function with ataxia and oscillopsia. Diagnosis is clinical with the finding of increased titers to Chlamydia, while treatment with steroids has been shown to hasten the symptoms.(11)

Sarcoidosis

This is a granulomatous disorder of unknown etiology which typically affects black females between the ages of 30-50. It is seen as multi-system disease, with the histological trademark of non-casseating granulomas as discrete lesions. It also has several characteristic laboratory findings such as hypercalcemia, hypergammaglobulinemia, elevated liver transaminases, and elevated levels of angiotensin converting enzyme which may allow objective clinical following of response to therapy. The most common site of involvement is by far pulmonary (88%) followed by lymphatic in 75% of the patients.(12) The chest x-ray will typically show hilar adenopathy. Other systemic manifestations include splenomegaly, diffuse neuropathies, intracranial mass involvement, and ocular pathology (optic neuritis). In the head and neck region, submandibular/submental/cervical adenopathy is frequently. The salivary glands are involved in approximately 20 -30% of the cases, showing either diffuse enlargement of granuloma infiltration. As a distinct clinical entity, Heerfordt's syndrome (a.k.a. uveoparotid fever) is seen as facial nerve paralysis, uveitis, and bilateral parotid swelling. The supraglottic region is also frequently affected with examination often revealing a pale, bluish, enlarged epiglottis as well as edematous, erythematous nodular masses along the mucosa. In addition, the paranasal sinuses, nose, and nasopharynx is involved in 10 - 20% of the patients with polypoid mucosa, nodular masses, and significant crusting. Diagnosis is made on biopsy specimens showing the non-casseating granulomas. Treatment ranges from observation in the asymptomatic patient to high dose steroids.(13)

Wegener's Granulomatosis

This is an autoimmune disease that is manifest as systemic necrotizing granulomas and vasculitis with a predilection for the upper and lower respiratory tracts and renal system. The pulmonary symptoms are almost universal with cough and hemoptysis, whereas the renal system is affected in approximately 40-50% of the cases, manifest as a focal glomerulonephritis.(14) Central and nervous system involvement is also seen in 20-30% of the cases, usually seen as polyneuritis, meningitis, or mononeuritis mulitplex. In the head and neck region, the paranasal sinuses/nose are the most frequently affected (60-80%) with chronic sinusitis, severe nasal crusting, septal perforation, and granulomatous destruction of tissue in these areas. While not as common, otological manifestations range from a serous otitis media to a severe sensorineural hearing loss secondary to cochlear vasculitis. Less commonly, subglottic stenosis may be seen in 8% of these patients.(15) Diagnosis is based on clinical findings, biopsy of involved tissue showing necrotizing granulomas/vasculitis, and laboratory evidence of c- ANCA. Treatment has been somewhat successful with prednisone, cyclophosphamide, and recently with trimethoprim/sulfamethoxazole.

Polyarteritis Nodosa

This is vasculitic disease that involves small and medium size arteries that usually involves those vessels supplying the tissues of the gastrointestinal tract, hepatobiliary system, kidney, pancreas, and skeletal tissues. The tissues involved undergo ischemia and necrosis secondary to the vasculitic process and manifest as myopathy, neuropathy, hepatic and renal failure, gastrointestinal bleeding, and progressive arthritis. In general, there are few head and neck manifestations; however, ischemia to the nasal and oral cavity/oral pharynx mucosa may cause ulceration. In addition, these patients may have serous otitis media, sensorineural hearing loss, and facial nerve paralysis.(16)

Churg-Strauss Syndrome

As a variant of polyarteritis nodosa, this disease is marked by allergic angiitis granulomatosis, asthma, and peripheral eosinophilia. The pulmonary system is almost invariably involved with 70% of these patients having nasal involvement, seen as nasal polyposis and allergic rhinitis.(17) This disease has three distinct clinical phases seen as:

Polymorphic Reticulosis/Lymphomatoid Granulomatosis

These are considered to by the same disease process. Histologically, they are characterized as an angiocentric infiltration of mature lymphocytes, immunoblasts, plasma cells, histiocytes, and a few atypical lymphoid cells. There is no accompanying granuloma or vasculitis. This distinguishes this disease entity from the vasculitides (such as Wegener's) in that there is no vessel destruction. While controversial, these disease may represent a precursor to a frankly malignant T-cell lymphoma. Systemically, many systems are involved including the central nervous system, pulmonary, renal, and the gastrointestinal tract. Regarding the head and neck manifestations, the early manifestation consists of a unilateral, localized ulceration of the nose or paranasal sinuses. This locally explosive ulcer progresses rapidly in its destruction to involve the adjacent sinuses, orbit, and palate. Rapid ulceration and necrosis generally results in spiking fevers and sepsis. While Wegener's granulomatosis also causes paranasal/nasal tissue destruction, it presents as a bilateral process, not unilateral. Diagnosis depends on biopsy. Treatment consists of radiation therapy in more localized disease to chemotherapy following a lymphoma protocol for disseminated disease.(19)

HEMATOLOGIC DISORDERS

Osler-Weber-Rendu (Hereditary Hemorrhagic Telangiectasia)

Transmitted as an autosomal dominant trait, this disease is characterized by telangiectatic lesions developing around puberty. Common sites include the gastrointestinal tract, the lungs and liver which may contain multiple, larger arteriovenous malformations, and in multiple areas in the head and neck regions. The nasal septum as well as the lateral nasal wall are frequently affected by these lesions which often results in frequent, severe episodes of epistaxis. In these patients, they may have gross destruction of the nasal septum secondary to the need for cauterization at the bleeding sites. Additionally, the nasal mucosa may be so involved with the lesions that septodermoplasty is often indicated. The lips and dorsum of the tongue are also involved in 60% of the cases; whereas, the palate, gingiva, buccal mucosa, and mucocutaneous junction is involved in approximately 20% of the cases.(20)

Acute Myelocytic Leukemia/Acute Lymphocytic Leukemia

Head and neck manifestations from leukemia are many fold. Epistaxis may occur secondary to thrombocytopenia or to a coagulopathy from liver infiltration. The temporal bone is also a well documented site of involvement, showing infiltration in the submucosa of the pneumatized area of the middle ear and mastoid, including the tympanic membrane and petrous apex.(21) Thus, these patients may present with otomastoiditis (chronic versus acute), tympanic membrane thickening, hearing loss, vertigo, and facial nerve paralysis. Gingival hyperplasia secondary to myeloid infiltration has been described for AML, while the lymphoid bearing tissues may be involved with ALL, especially the tonsils. Petechia and hemmorhagic lesions may also be noted in the oral cavity secondary to thrombocytopenia. As a distinct clinical entity, agranulocyte angina is marked as extreme pain in the oral cavity with a relatively unremarkable clinical examination.

Hodgkin's Lymphoma/Non-Hodgkin's Lymphoma

Lymphoma is the most common form of pediatric malignancy, many presenting to the otolaryngologist initially because of head and neck involvement. Hodgkin's lymphoma is typically found in young adults or adolescents and is characterized as a lymphoreticular malignancy with Reed-Sternberg cells. These cells are seen as large, multi-nucleated cells having perinucleolar halos and eosinophilic cytoplasm. This disease begins in a single lymph node and then progresses in a contiguous pattern. The major head and neck manifestation of Hodgkin's lymphoma is the presence of painless lymphadenopathy in the cervical, supraclavicular, and mediastinal areas.(22) While adenopathy is clearly the most common manifestation, extranodal involvement occurs in 10% of cases (Hodgkin's and Non-Hodgkin's) includes infiltrates in tonsil (40%), nasopharynx (18%), paranasal sinuses/nose (13%), oral cavity (10%), salivary gland (9%), and base of tongue (8%).(23) Non-Hodgkin's lymphoma, as contrasted to Hodgkin's, is more commonly a disease of pre-adolescent children with involvement of the lymphatics in a non-contiguous fashion. In addition, there is often evidence of disseminated disease at initial presentation, with only a small percentage having head and neck manifestations. There are three histologically distinct subtypes: undifferentiated (Burkitt's and Non-Burkitt's lymphoma), lymphoblastic, and large cell. In these lymphomas, the lymphoid tissue of Waldeyer's ring may be involved.

Plummer-Vinson's Syndrome

This syndrome has been referred to as sideropenic dysphagia and is a disease entity marked by dysphagia, hypopharyngeal and esophageal webs, weight loss, and iron deficiency anemia. It usually affects females in the 30-50 year old age group.(24) The otolaryngological manifestations include atrophic glossitis secondary to atrophy of the filiform papillae, angular chelitis, and hyperkeratotic lesions on the oral mucosa. The webs in the hypopharynx are typically between the cricoid and the thoracic esophagus. They begin as anteriorly located webs but become circumferential. There is an increased incidence of carcinoma located proximal to the webs, likely secondary to chronic inflammation in this region.

METABOLIC DISORDERS

Gout

This is a disease entity seen as a disorder of uric acid metabolism, which typically results in an episodic, self-limited monoarticular arthritis. While head and neck manifestations are rare, gouty arthritis and tophaceous deposits may manifest in this area. Involvement of the cricoarytenoid joint presents as dysphagia, pain, hoarseness, and possibly stridor/airway obstruction depending on possible fixation of the cord. The helical rim of the pinna is the usual location of involvement the tophaceous deposit, which is marked as uric acid crystals with associated foreign body reaction

Thyroid Disorders

Hypothyroidism has several causes but the clinical manifestations of having reduced levels of thyroid hormone produces a similar clinical picture. Systemic symptoms and signs consist of myxedema, muscle cramps, impaired memory, lethargy, constipation, cold intolerance, bradycardia with associated EKG changes, and prolonged reflexes. For the otolaryngologists, these patients may present with hoarseness secondary to myxedema of the vocal cords, nasal obstruction secondary to edema of the nasal mucosa, alopecia which may affect the lateral third of the eyebrows, and a thickened tongue. Hyperthyroidism also has several head and neck manifestations. The systemic manifestations includes hyperreflexia, heat intolerance, anxiousness, and cardiac arrhythmias, Regarding the head and neck region, thyroid exophthalmos is seen in Grave's disease. In addition to the exophthalmos , there may be decreased ocular motility. The ocular pathology is secondary to an infiltration of the muscles and periorbital tissues with an abnormal mucopolysaccharide substance as well as a lymphocytic infiltration.(25)

Diabetes Mellitus

Poorly controlled diabetics are at greater risk of opportunistic type infections, secondary to granulocyte qualitative dysfunction. For instance, these patients may present with oral cavity/pharyngeal candidiasis. These patients may complain of vertigo/dizziness, usually related to elevated blood sugar as well as to autonomic dysfunction causing severe orthostatic hypotension, and may have a sensorineural hearing loss secondary diabetic micorangiopathy. Of special importance for the otolaryngologist is the clinical entity of malignant (necrotizing) otitis externa caused by Pseudomonas aeriginosa. The infection starts after only minor trauma to the external canal which later manifests as severe otalgia. Examination of the affected ear shows signs of inflammation, with redness, swelling, and tenderness. In addition, there may also be an area of granulation tissue located at the floor of the ear canal along the junction of the bony and cartilaginous portions, representing osteitis of the lateral lip of the tympanic bone.(26) Later stages of malignant otitis externa may present with cranial nerve palsies secondary to cranial base osteitis. In addition, the infection may spread posteriorly to the stylomastoid foramen causing facial nerve paralysis. Treatment consists of meticulous control of the diabetes, intravenous antibiotics (usually an aminoglycoside and a semisynthetic penicillin), antibiotic ear drops, and debridement of infected tissue. Hyperbaric oxygen therapy has also been proven to improve the healing time.

NEUROLOGIC DISORDERS

Multiple Sclerosis

Multiple sclerosis is a demyelinating disease of the central nervous system that has a remitting and exacerbating course. In approximately 20% of the patients, the initial manifestation of multiple sclerosis is blurred or loss of vision secondary to demylientation of the optic nerve. Additionally, internuclear ophthalmoplegia is another early manifestation secondary to demylientation of the medial longitudinal fasiculus , which is seen as the inability to attain conjugate gaze because the lateral rectus and contralateral medial rectus are incoordinated. Vertigo is also a frequent finding in this disease, affecting up to 50% of the patients with multiple sclerosis and being the initial manifestation in 7-10% of these patients. It should be noted that while the nystagmus, usually horizontal, is found in 70% of the patients, but the finding of pendular fixation nystagmus is helpful in that it is rarely found with other pathology.(27) With regard to nystagmus, it is a component of Charcot's triad in multiple sclerosis, along with scanning speech (dysarthria secondary to cerebellar involvement) ,and an intention tremor.(28) Hearing loss may be found in up to 10% of the patients. Diagnosis of MS depends on the MRI to identify foci of demyelination within white matter; whereas, laboratory analysis may reveal elevated gamma globulin levels and elevated myelin basic protein. There is no definitive treatment of MS, although steroids and adrenocorticotropic hormone have been found to hasten the remission of the clinical manifestations.

Myasthenia Gravis

Likely an autoimmune disease caused by IgG directed at acetylcholine receptors, this disease is marked by weakness and fatigue of the striated muscles. Marked by frequent remissions and exacerbations, these patients will demonstrate symptoms resulting from weakened facial, laryngeal, and pharyngeal muscles. Dysphagia may be a presenting complaint as the cricopharyngeus is frequently involved. The diagnosis may be made with relief of muscle weakness after the administration of edrophionium which inhibits acetylcholinesterase which then allows an increased amount of acetylcholine at the receptor site. Treatment is directed at using anticholinesterase medications, such as pyridostigmine. It should be mentioned that in approximately 10% of these patients with MG, there may be an associated thymoma.(29)

Guillian-Barre Syndrome

This is an acute, fulminant polyneuropathy which usually has a preceding viral illness approximately 1-3 weeks earlier; although, in approximately 5-10% of the reported cases, a surgical procedure took place 1-4 weeks prior to the onset of disease.(30) Of those felt to be virally induced, herpetic infections (cytomegalovirus and Epstein-Barr virus) are believed to account for a large number of the cases. The clinical features of Guillian-Barre syndrome is an areflexic motor paralysis with mild sensory disturbances. Approximately 25% of these patients require mechanical ventilation secondary to diffuse involvement of the muscles of respiration, but the overall prognosis is excellent with 85% of the patients making complete or nearly complete recovery. Regarding the head and neck manifestations, facial nerve paralysis may also be seen with this syndrome and may be bilateral. The Fisher variant of Guillian-Barre syndrome begins with weakness of the facial and neck muscles prior to limb weakness, as opposed to the usual later manifestation. Treatment consists of supportive care with some success with the use of plasmapheresis.(31)

Amyotrophic Lateral Sclerosis

This is a disease characterized by progressive loss of motor neurons in the motor cortex and in the anterior horn cells in the spinal cord. Generally, it is found in patients over the age of 50, with men being more frequently affected. Its first manifestations are asymmetric muscle weakness, fatigue, and cramping. As the disease progresses, virtually every muscle group will show signs of weakness and later atrophy. In the head and neck region, muscular dysfunction will cause a variety of problems of the patient. For instance, the patient may have difficulty with mastication, deglutition, and facial movement. The involved muscle groups show signs of atrophy and fasiculations as the disease continues. This disease is relentlessly progressive without any identifiable cure.

NUTRITIONAL DISORDERS

Hypovitaminosis A

Deficiency may result from either endemic lack of this vitamin in the diet or form protein-calorie malnutrition which results in a defective release from the liver of retinol-binding protein.(32) The initial manifestation is that of night blindness later followed by degenerative changes of the retina and necrosis of the cornea (keratomalacia) with subsequent lens extrusion. Stomatitis and xerostomia are also frequent manifestations.(33)

Hypovitaminosis B1 (Thiamine)

Deficiency of thiamine is marked by the clinical syndromes of beriberi and the Wernicke-Korsakoff syndrome. In beriberi, a "wet" form exists in which the patient may has clinical evidence of congestive heart failure with diffuse edema, and a "dry" form in which the central and peripheral nervous system is principally involved. The dry beriberi is seen as a peripheral neuropathy in which the patient may have serious gait instability and dysequilibrium that may be construed as vertigo. In addition, the distal extremities have sensory loss. Beriberi generally occurs in rice-predominate diets. On the other hand, the Wernicke-Korsakoff syndrome is typically seen in alcoholics who typically have a protein poor/carbohydrate rich diet It is seen as marked by memory loss of the immediate past which results in confabulation. Regarding the head and neck manifestations, these patients may present with Wernicke's encephalopathy which is seen as nystagmus (usually horizontal), lateral rectus muscle palsies, and diplopia. These patients may also have ataxia, fever, progressive mental deterioration, and profound emesis.(34)

Niacin/Nicotinic Acid Deficiencies

Deficiencies of nicotinic acid produce clinical findings collectively referred to as pellegra. It is a chronic wasting disease associated with dermatitis, diarrhea, and dementia. For the otolaryngologists, this deficiency produces a widespread inflammation of the mucosal surfaces which leads to glossitis, angular stomatitis, and cheilosis. Burning tongue pain is often the first clinical sign of niacin deficiency. This inflammatory reaction of the mucosal surfaces also explains the diarrhea associated with pellegra.

Deficiency of Riboflavin

This deficiency is characterized by its oral manifestations. This syndrome is characterized by sore throat, hyperemia and edema of the pharyngeal and oral mucous membranes, cheilosis, angular stomatitis, and glossitis. In addition, these patients may also have seborrheic dermatitis and normocytic anemia secondary to red cell hypoplasia of the bone marrow.(35)

Vitamin B12 Deficiency

Deficiency of this vitamin is seen systemically as a megaloblastic anemia, which may also be seen with folic acid deficiency. Clinically, these patients often present with painful atrophy of their oral mucosa, lingual papillae, and tongue. In addition, they may have recurrent aphthous ulcerations in the oral cavity.(36)

INFECTIOUS DISEASES

Tuberculosis

Disease caused by Mycobacterium tuberculosis is spread from person to person by inhalation of an airborne droplet containing the organism. In the overwhelming majority of the patients, the primary infection is asymptomatic; however, inoculation initiates an inflammatory response with a cell mediated hypersensitivity component developing over time. It is this immune response that sequesters the tubercle bacilli and prevents multiplication or spread. The healing process occurs, leaving a calcified granuloma referred to as a ghon complex (in conjunction with hilar lymph node). In approximately 95% of those exposed, the disease is limited; however, in 5% of the patients, the clinical manifestations of tuberculosis occur, likely re-activated at a later time. The clinical manifestations of TB are extensive, but pulmonary disease is an integral component. Regarding the head and neck manifestations, cervical lymphadenopathy is the most common and is referred to as scrofula. The lymph nodes are multiple, matted, and non-tender, with usual bilateral involvement of the posterior triangles. The larynx is involved in approximately 1% of the patients, likely secondary to bronchogenic spread. The arytenoids are involved with the greatest frequency followed by the true vocal cord, epiglottis, false vocal cord, and the subglottic area. The lesions may be edematous, granulomatous, or ulcerated. Oral cavity lesions (tuberculomas) are found in 0.5 to 1.5% of the patients with the tongue being the most frequently affected (50%). Although far less common, otologic involvement may be seen as multiple tympanic membrane perforations accompanied by a thin, watery otorrhea. Diagnosis requires PPD, chest x-ray, and sputum showing acid fast bacilli. Treatment is with anti-tuberculosis agents

Atypical tuberculosis

Caused by M. kansaii, M. scrofulaceum, M. intracellularis, and M. fortuitum. Transmission is from soil to mouth and eye. Usually affecting children, a corneal ulceration is the usual manifestation followed by scrofula in the anterior cervical, preauricular, and submandibular regions. The lymph nodes are discrete, separate, and have the potential to form an abscess. Diagnosis is by excisional biopsy of the involved lymph node, with cultures and staining showing the bacilli. Treatment consists of anti-tuberculous agents/antibiotics, dependent on the culture sensitivities.

Mycobacterium leprae

Causes leprosy (Hansen's disease) which is far more prevalent in tropical climates. There is a spectrum of disease ranging from a tuberculin form to the lepromatous form. The tuberculoid form consists of granulomatous involvement of the peripheral nerves producing severe myalgias and muscle atrophy. In this setting, the facial nerve may also be involved. In contrast, the lepromatous form has no neurological involvement but is classically seen as widespread cutaneous lesions. These mucosal lesions may cause septal perforations as well as destruction of support mechanisms of the nose. Lateral loss of the eyebrows are a common finding. Diagnosis is through culture of involved tissue, demonstrating the organism. Treatment is usually with dapsone.(37)

Syphilis

Caused by the spirochete Treponema pallidum, this disease has several head and neck manifestations correlating with the specific stage of the disease. In the primary stage, a painless ulcer exists at the site of innoculum. While the chancre is typically located in the genital area, it may found on the lips, tongue, or tonsil. During the secondary stage, mucocutaneous lesions predominate. These may be found in the oral cavity/oral pharynx and along the nasal mucosa. Other manifestations during this stage includes rhinitis, laryngitis, pharyngitis, otitis media, and alopecia. This stage then spontaneously resolves but has the potential to recur at a later time. The tertiary stage occurs in 1/3 of the patients with syphilis and is marked by the gumma lesion which represents the granulomatous reaction to the organism. Nasoseptal involvement occurs commonly, resulting in perforation or saddle nose deformity, as is hard palate perforations. Ulcerations in the larynx may also occur resulting in chrondritis/perichondritis from secondary bacterial infection. The temporal bone is affected when the gummatous lesion produces an obliterative endarteritis. There is gradual loss of the membranous labyrinth resulting in sensorineural hearing loss seen as fluctuating, bilateral, and sudden with possible accompanying vertigo. For the clinician, there are two signs which may be present reflecting the underlying pathology of softening of the otic capsule. Hennebert's sign shows nystagmus and vertigo as positive pressure is applied to the ear canal, while Tulio's phenomenon is seen as nystagmus following exposure to loud noise. Congenitally acquired syphilis has its own set of clinical manifestations including a saddle nose deformity, frontal bossing, short maxilla, Hutchinson's incisors, mulberry molars, mental retardation, and sensorineural hearing loss. In congenital syphilis, a triad of SNHL, interstitial keratitis, and notched incisors is referred to as Hutchinson’s triad. Treatment consists of penicillin G.

Lyme Disease

Caused by Borellia burgdorferi and spread through a tic vector, this disease is endemic to the Northeastern portion of the United States. Clinically, at the site of innoculation an annular, expanding red lesion may be found, referred to as erythema chronicum migrans. The course is then marked as malaise, fever, myalgias, generalized lymphadenopathy, oligoarticular arthritis (45%), cardiac conduction abnormalities secondary to myocarditis (8%), possible encephalitis or radiculoneuritis and cranial neuropathies. Of interest to the otolaryngologist, facial nerve paralysis may be unilateral or bilateral and associated with other cranial neuropathies, such as CN III and CN V. It has been found that most of these neuropathies will generally resolve in 6 12 months; however, treatment with beta lactamase antibiotics that may decrease the overall time for resolution.(39)

Cat Scratch Disease

This is caused by an intracellular, gram negative bacilli which requires special staining (Warthin-Starry) for detection. Cat exposure is identified in a large number of cases. It is generally found only in children. The clinical manifestation is that of a vesicular, papular , or pustular lesion at the site of innoculation with regional lymphadenopathy. In the head and neck region, cervical lymphadenopathy is commonly found. Histologically, a non-casseating granulomatous type reaction may be found. This disease is self-limited, with incision and drainage as needed for severe abscess formation. In general, the mass will resolve in 2-6 months.

Actinomycosis

Classed between a bacteria and a fungi, Actinomyces israelli is a micoraerophillic gram-positive organism that is a normal oral inhabitant (especially in the tonsillar crypts). It may produce a granulomatous suppurative cervical adenitis or a cervicofacial infection. In the cervicofacial form, there is typically an indurated, non tender subcutaneous mass in the anterior cervical or submandibular triangle with multiple draining sinus tracts. Infection appears to be promoted by those patient with severe periodontal disease and dental caries. The systemic complaints are frequent with fever, weight loss, vomiting, night sweats, and general malaise. Demonstration of sulfur granules on microscopic examination makes the diagnosis. These are granules are tangle of filaments of tissue cells and lipid-laden macrophages. Treatment consists of long-term parenteral antibiotics with surgical debridement necessary in extreme cases to remove necrotic tissue.(39)

Aspergillosis

Caused by inhalation of spores of Aspergillus fumigatus, a ubiquitous fungus, it usually causes a self-limiting acute pneumonitis in an otherwise healthy patient. It may, however, present as a systemic disease with major otolaryngological manifestations and may be classified as allergic, non-invasive, and invasive. In the allergic form, it appears as an analogue to the allergic bronchopulmonary aspergillosis. It accompanies and exacerbates asthma and clinically is seen as thick, tenacious nasal secretions with demonstrable calcifications on CT scan. The epithelium and bone of the involved sinus is spared, with the fungus localized to the overlying blanket of mucus. Non-invasive aspergillosis presents as a unilateral sinusitis with extremely thick secretions, but without the clinical evidence of bony erosion or asthma. In the immunocompromised host, the invasive form of aspergillosis may be found. There is facial hypesthesia, opthalmoplegia, proptosis, bony loss and destruction as seen on CT scan, and possible visual loss. Of note, an aspergilloma may be found within a cavitated pulmonary lesion or may be found within a sinus, especially the maxillary sinus. Treatment of aspergillosis is surgical debridement with use of intravenous amphotericin B. In allergic aspergillosis, the disease may be ameliorated with systemic steroids.(40)

HIV/AIDS

The HIV/AIDS patient presents to the otolaryngologist with a multitude of problems in the head and neck, including frequent acute infections of the normal human pathogens, opportunistic infections, neurological complaints, and neoplastic processes. As the degree of immunodeficiency increases, the spectrum of disease that involves the head and neck also increases.

DERMATOSES

Several dermatological conditions affect the face and scalp region in the infected patient. Molluscum contagiosum is often seen in the symptomatic HIV positive patient. It is characterized by small pearly, umbilicated papules that have a predilection for the eyelids. Treatment consists of excision versus cryotherapy. Another common skin disorder is seborrheic dermatitis that is often found on the scalp and face, affecting approximately 83% of these patients.(41) These lesions are white scaly plaques or patches that may have an element of erythema or inflammation. Bacillary angiomatosis is found in the more immunosuppressed HIV patient and requires histology for diagnosis as an organism is rarely cultured. This lesion is often found on the face and presents as a non-specific subcutaneous nodule or as a friable papule. Oral erythromycin is an effective treatment. Herpes zoster may present in a specific dermatomal pattern on the head or neck. If the geniculate ganglion is involved in the herpetic infection, the Ramsay Hunt syndrome is seen and is manifest as vesicles on the ear, oral mucosa, tonsils, pharyngeal mucosa, posterior third of the tongue, facial palsy, loss of taste, decreased salivation, palatal paralysis, and pain.(42) Acyclovir is the treatment for this viral infection. Rarely, the HIV/AIDS patient may present with pustular or granulomatous lesions involving the skin of the head and neck that represent cutaneous Cryptococcus on histopathologic or culture identification. Finally, Kaposi's sarcoma is often manifest as violaceous papular or ulcerated skin lesions on the head and neck. While the gold standard for treatment of this neoplasm is controversial, the Argon and CO2 lesions have been helpful in control of local disease as well as low-dose radiation therapy, chemotherapy (i.e. vincristine or vinblastine), and immunotherapy (i.e. alpha-interferon).

OTOLOGIC CONDITIONS

Several otological conditions also affect the HIV/AIDS patient. While the external auditory canal is often affected by some of the dermatological problems discussed above, such as Kaposi's sarcoma and seborrheic dermatitis, more often this subset of patients are affected by serous and acute otitis media. In the pediatric population with an already altered eustachian tube function coupled with a depressed immune system, they have an increased risk of middle ear infection. In the adult patient, adenoid hypertrophy that often occurs with this disease increases the likelihood of eustachian tube dysfunction, therefore contributing to an increase in otitis media. In addition to the normal pathogens for middle ear disease, patients with AIDS may harbor Pneumocystis carnii, candida, staphylococcus, or pseudomonas on tympanocentesis. Although not clearly understood, several patients may have a mild to moderate sensorineural hearing loss perhaps secondary to a central or peripheral nervous system viral infection.(43)

NASAL DISORDERS

The nose and paranasal sinuses are also frequent sites of pathological processes in the HIV/AIDS patient. A common complaint is nasal obstruction and thick postnasal rhinnorhea. This may be secondary to allergic rhinitis of which these patients often have a hyperactive allergic response, nasopharyngeal lymphoid tissue hypertrophy, or a neoplastic process in the nose or nasopharynx (i.e. Kaposi's sarcoma, lymphoma). In addition, acute and chronic sinusitis is often a problem caused by the usual pathogens as will as more unusual ones as the immunusupression increases, such as legionella, candida, cryptococcus, acanthamoeba.

ORAL CAVITY DISORDERS

The oral cavity and oropharynx are also a frequent area displaying disease in these immunosuppressed patients. Oral cavity/pharynx candidiasis infection is the most common manifestations of HIV/AIDS infection. The most common form of oral candidiasis is pseudomembranous candidiasis (a.k.a. thrush) that is characterized by plaques that may be easily removed, leaving an erythematous base. The less common form is the atrophic candidiasis that is seen as flat, atrophic patches on the tongue, palate, or buccal mucosa; whereas, the candida leukoplakia is seen as hyperkeratotic lesions that may not be mechanically removed. Angular chelitis is seen as erythematous fissures in the corner of the mouth which is often seen in patients with oral candida infection. Diagnosis is based on the basic examination along with a KOH prep if needed, while treatment consists of a basic topical solution of nystatin to oral or parenteral anti-fungals. Stomatitis caused by herpetic lesions versus aphthous ulcers are also common. Herpetic stomatitis is seen as several ulcerative, punched out lesions occurring on any mucosal surface, but with a predilection for the palatal, labial, buccal, or gingival surfaces. These may coalesce to form an extremely large ulcerative lesions. Acyclovir and topical steroids help to attenuate the local symptoms.

Aphthous ulcers are non-viral in orgin, typically single, and usually found on "mobile" mucosal surfaces. Steroid therapy (topical versus intralesional) may alleviate local symptoms. Hairy leukoplakia is a lesion that is noted seen almost exclusively in the HIV infected patient and is seen as a corrugated, whitish lesion along the anterior lateral border of the tongue. Therapy is not usually indicated unless it becomes secondarily infected; however, it is a relatively reliable prognosticator for the development of AIDS (50 % at 16 months/80% at 30 months). Lymphoid hyperplasia in Waldeyer's ring is often found in the patients.

Of note, malignancies such as lymphoma (non-Hodgkin's>>>Hodgkin's) may be harbored in these tissues, especially in the patient with an ulcerated lesion on the tonsil or tonsillar asymmetry. Other neoplasm's within the oral cavity/oral pharynx in the HIV/AIDS patient is the previously described Kaposi's sarcoma. These have a violaceous color, may be flat or nodular, and have a predilection for the hard palate. Finally, the immunosuppressed patient may have aggressive periodontal disease that may result in a necrotizing ulcerative gingivitis with associated gingival recession. Treatment is directed at diligent oral hygiene with frequent anti-bacterial mouthwashes and prophylactic flagyl.

SALIVARY GLAND DISORDERS

Salivary gland disease is also frequently seen. The spectrum of disease ranges from xerostomia with histolopathologic findings similar to Sjogren's syndrome, to generalized parotid gland enlargement (reported in 30% of the pediatric population) secondary lymphocytic invasion into the gland parenchyma, and to parotid masses caused by Kaposi's sarcoma, Non-Hodgkin's lymphoma, benin lymphoepithelial cysts, or else to the usual parotid neoplasms. Of note, lymphoepithelial cysts are common in the HIV/AIDS population and are usually bilateral and located in the tail of the parotid gland. Treatment may be difficult as they often recur despite surgical excision or aspiration. Sclerosis with a variety of agents, such as tetracycline, has shown some success.

VIRAL DISORDERS

Measles (Rubeola)

Caused by a paromyxovirus, this viral infection has become less of a medical issue with the advent of vaccination programs. It is, however, a highly contagious infection manifest by coryza, conjunctivitis, and a generalized cutaneous erythematous rash. In the head and neck areas, early in the infection, small, spotty, exanthematous lesions are noted on the buccal mucosa, referred to as Koplick's spots. In addition to producing a pharyngotonsillitis in the course of the disease, it was a cause of acquired sensorineural hearing loss in children, accounting for approximately 3-10% of acquired causes.(44) Although only .1% of children with measles actually develop hearing loss along the course of the disease, it is typically bilateral, profound in 45%, and mild to moderate for the remainder.

Herpes Simplex Virus

Primary herpes simplex virus infection occurs in young children, typically between the ages of 10 months and 3 years. Transmitted by mucus or saliva, the incubation time lasts from 2-12 days after which the child develops a system illness characterized by malaise, fever, and pharyngitis. Examination of the pharynx reveals vesicular lesions covered with a black crust with possible accompanying shallow tonsillar ulcers with gray exudate. In the immunocompromised child, a disseminated form of primary HSV may occur with resulting meningioencephalitis. Following the primary infection, the HSV resides latent in the sensory ganglion innervating the oral cavity or oral pharyngeal sites originally affected. Recurrence at later stages results in a limited gingivostomatitis, with characteristic multiple punched ulcers.

Infectious Mononucleosis

Epstein-Barr virus is implicated in 80-95% of the cases of mononucleosis; however, other viruses such as cytomegalovirus, human immunodeficiency virus, adenovirus, rubella, and hepatitis A may also produce a mononucleosis like syndrome. It is manifest as a systemic prodromal phase of 2-5 days of malaise and fatigue followed by an exudative pharyngotonsillitis, cervical lymphadenopathy (typically posterior), and hepatomegaly (10%), and splenomegaly (50%). The hepatosplenomegaly is usually manifest at the 2-4th week of the illness, where splenic rupture is a potentially serious complication of the disease. Laboratory evidence of lymphocytosis with many atypical cells are commonly seen as well as easy detection on commercially available Mono-spot test (heterophil positive). Therapy is strictly supportive.

Mumps

Due to more widespread vaccination programs, this viral illness is not a common entity. It is the most common viral disorder involving the salivary gland and was considered to be the most common cause of parotid gland swelling. Generally affecting children 4-6 years of age, it present with systemic complaints of fever, malaise, myalgias, and headache. Following an incubation time of 2-3 weeks, there is pain and swelling of one or both parotid glands. This is a self-limited infection and relies on supportive treatment. Major complications may occur, however, consisting of pancreatitis, orchitis, meningitis, and sudden deafness. While the hearing loss only affects 5 of 10,000 patients with measles, it tends to be unilateral in 80% of the cases with more pronounced hearing loss at the higher frequencies.(45) Unfortunately, the hearing loss is typically permanent.

BIBLIOGRAPHY

1. Harrison's Principles of Internal Medicine. Twelfth Edition. McGraw-Hill. 199I pg. 1437.

2. Brooker, DS. Rheumatoid Arthritis : Otorhinolaryngological Manifestations. Otolaryngologic Clinics of North America, 1988.

3. Paparella, MM., et al. Otolaryngology. Third Edition. WB Saunders. 1991. pg. 810.

4. Bailey, BJ., et al. Head and Neck Surgery-Otolaryngology. J.P. Lippincott. 1993. pg. 168.

5. Cummings, CW., et al. Otolaryngology-Head and Neck Surgery. Second Edition. Mosby Year Book. 1993. pg. 755.

6. Ibid. pg. 2300.

7. Kelly, WN. Textbook of Rheumatology. Second Edition. WB Saunders. 1985.

8. Bailey, BJ., et al. Head and Neck Surgery-Otolaryngology. J.P. Lippincott. 1993. pg. 157.

9. Ibid.

10. Ibid.

11. Paparella, MM., et al. Otolaryngology. Third Edition. WB Saunders. 1991. pg. 810.

12. Bailey, BJ., et al. Head and Neck Surgery-Otolaryngology. J.P. Lippincott. 1993. pg. 168.

13. Ibid.

14. Ataman, M., et al. Wegener's Granulomatosis: Case Report and Review of the Literature. Rhinology. Volume 32. 1996.

15. Kornblut, AD. Symposium of Granulomatous Disorders of the Head and Neck. The Otolaryngologic Clinics of North America. Vol 15 Number 3. WB Saunders.

16. Ibid.

17. Bailey, BJ., et al. Head and Neck Surgery-Otolaryngology. J.P. Lippincott. 1993. pg. 169.

18. Cummings, CW., et al. Otolaryngology-Head and Neck Surgery. Second Edition. Mosby Year Book. 1993. pg. 755.

19. Ibid, pg. 717.

20. Ibid, pg. 1178.

21. Ibid, pg. 2915.

22. Marion, J. Diagnosis and Treatment of Lymphomas. In: Comprehensive Management of Head and Neck Tumors. WB Saunders. 1987., pg. 1849.

23. Ibid, pg. 1829.

24. Cummings, CW., et al. Otolaryngology-Head and Neck Surgery. Second Edition. Mosby Year Book. 1993. pg. 1223.

25. Harrison's Principles of Internal Medicine. Twelfth Edition. McGraw - Hill. 199I pg. 1703.

26. Bailey, BJ., et al. Head and Neck Surgery-Otolaryngology. J.P. Lippincott. 1993. pg. 1550.

27. Ibid, pg. 101.

28. Ibid.

29. Ibid.

30. Harrison's Principles of Internal Medicine. Twelfth Edition. McGraw-Hill. 1991 pg. 2103.

31. Ibid.

32. Paparella, MM., et al. Otolaryngology. Third Edition. WB Saunders. 1991. pg. 814.

33. Ibid.

34. Harrison's Principles of Internal Medicine. Twelfth Edition. McGraw - Hill. 199I pg. 437.

35. Ibid.

36. Ibid.

37. Bailey, BJ., et al. Head and Neck Surgery-Otolaryngology. J.P. Lippincott. 1993. pg. 180.

38. Harrison's Principles of Internal Medicine. Twelfth Edition. McGraw - Hill. 199I pg. 668.

39. Bailey, BJ., et al. Head and Neck Surgery-Otolaryngology. J.P. Lippincott. 1993. pg. 181- 182.

40. Cummings, CW., et al. Otolaryngology-Head and Neck Surgery. Second Edition. Mosby Year Book. 1993. pg. 2329.

41. Bailey, BJ., et al. Head and Neck Surgery-Otolaryngology. J.P. Lippincott. 1993. pg. 776.

42. Ibid, pg. 103.

43. Ibid, pg 778.

44. Ibid, pg 1748.

45. Ibid.