به نام خداوند دادار پاک پدیدآور آدم از آب و خاک

1. به نام خداوند دادار پاک پدیدآور آدم از آب و خاک Otologic Manifestationsof Systemic Disease

2. granulomatous and infectious diseases, • neoplasms, • disorders of bone, • storage and metabolic diseases, • Autoimmune and immunodeficiency disorders.

4. I-GRANULOMATOUS AND INFECTIOUS DISEASES 1-LANGERHANS CELL HISTIOCYTOSIS formerly called histiocytosis X,(Lichtenstein ) eosinophilic granuloma, Hand-Schuller-Christian disease, Letterer-Siwe disease a proliferation of cytologically benign histiocytes Etiology: Idiopathic,, immunologic dysfunction that leads to unchecked proliferation of pathologic Langerhans cells -Unifocal eosinophilic granuloma  in children and youngadults, malepredominance a solitary osteolytic lesion in the femora, pelvis, scapulae, vertebrae, ribs, mandible, maxilla, or skull, which includes the temporal bone. The lesion may be asymptomatic, or it may cause pain, local swelling, or pathologic fracture. No systemic manifestations have been reported

5. --clinical course is typically benign, the prognosis is excellent, spontaneous regression may occur. Local curettage with or without low-dose irradiation (approximately 60 Gy) temporary splinting or casting may be necessary for weight bearing bones. Follow-up examination with a radiographic skeletal survey almost always found within 1 year. --Hand-Schuller-Christian disease multifocal form of LCH usually occurs in children younger than 5 years of age multifocal osteolytic lesions with limited extraskeletal involvement of skin, lymphnodes, and viscera Systemic manifestations fever, anorexia, recurrent upper respiratory infections, anterior cervical lymphadenopathy, otitis media, and hepatosplenomegaly The classic triad osteolyticskull lesions, exophthalmos as a result of orbital bone involvement, and diabetes insipidus secondary to pituitary disease may be seen in 25% of patients

6. Chest radiograph may show diffuse pulmonary infiltration, particularly in central and perihilar areas. Hilar lymphadenopathy is rare. Diagnosis requires biopsy of an accessible lesion. Spontaneous regression may occur, but the disease is typically chronic, and low-dose chemotherapy may be required to control systemic manifestations. Letterer-Siwe disease a disseminated form of LCH in children younger than 3 years -diffuse involvement of multiple organs --- fever, seborrheic or eczema-like rash, oral lesions, lymphadenopathy, hepatosplenomegaly, multiple bony lesions, diffuse replacement of marrow with resulting blood dyscrasias, and pulmonary infiltration with respiratory failure. The disease is virulent, with a poor prognosis and a high mortality rate. Treatment consists of varying combinations of corticosteroids and cytotoxic drugs such as methotrexate, mercaptopurine, vincristine, vinblastine, chlorambucil, cyclophosphamide, and etoposide. High-dose chemotherapy and radiation followed by bone marrow transplantation or hematopoietic stem cell transplantation has been reported to be successful in a few advanced refractory cases of LCH

7. Otologic Manifestations The mastoid is a common site of involvement in LCH. When small, the lesion is asymptomatic. As it expands, it may manifest in several ways: by erosion of the posterior bony canal wall; by erosion through the cortex of the mastoid, zygomatic, or squamous portions; or by secondary infection The otic capsule and facial nerve are relatively resistant. Although sensorineural hearing loss (SNHL), vertigo, and facial nerve paralysis can occur, they are infrequent. Similarly, extension beyond the temporal bone to the jugular fossa and skull base is rare. The reported incidence of otologic manifestations in patients with LCH is 15% to 61%, and they may be the first sign of the disease. The most common symptom is otorrhea, followed by postauricular swelling, hearingloss, and vertigo. The most common sign is granulation tissue or aural polyps in the external auditory canal. The disease may manifest with perforation of the tympanic membrane, otitis media, otitis externa, fistula between the mastoid and the external canal, or nontender postauricular swelling. Occasionally, inner ear symptoms and a positive fistula test are found in the presence of an intact tympanic membrane.

8. The disease often mimics chronic otitis media, and mastoid surgery is frequently performed before the diagnosis is made. Diagnosis of LCH is suggested by 1) an inflammatory disorder of the middle ear and mastoid that does not respond to routine antibiotic therapy, 2) bilateral destructive ear disease, 3) an elevated erythrocyte sedimentation rate (ESR) in the absence of acute infection, 4) exuberant granulation tissue after mastoid surgery with a persistently draining cavity, 5) associated skin and systemic lesions. Radiographs show destructive lesions in the mastoid and temporal bones The diagnosis is established by biopsy; because the surface of the granulation tissue often shows infection, necrosis, and fibrosis, tissue should be acquired from deeper parts of the lesion.

9. Multiple eosinophilic granulomas in a 32-year-old woman. Two lytic lesions of the skull show beveled edges (arrows) and nonsclerotic margins, which are typical of this disease

10. Irregular lytic lesion in the mastoid bone (arrows) of a 13-year-old boy with unifocal eosinophilic granuloma

11. I-GRANULOMATOUS AND INFECTIOUS DISEASES 2-TUBERCULOSIS The incidence of tuberculous otitis media has decreased dramatically. During the early part of the twentieth century, 1.3% to 18.6% of all cases of chronic otitis media were reportedly caused by tuberculosis, whereas more recent studies report tuberculous otitis media rates of 0.05% to 0.9%. The last 20 years have witnessed an increase in incidence of tuberculosis, however, caused in part by the aggressive nature of tuberculosis in individuals infected with AIDS (HIV) And by an emerging resistance to antituberculosis drugs. Mycobacterium tuberculosis is the infective organism in most cases; occasionally, atypical mycobacteria (e.g., M. avium and M. fortuitum) are responsible. Tuberculosis of the middle ear and mastoid may occur as a result of hematogeneous or lymphatic spread or by extension to the middle ear cleft through the eustachian tube. Direct inoculation through a perforation of the tympanic membrane is also possible. Middle ear involvement in the absence of active pulmonary disease is rare but may occur

12. During the early stages of tuberculous otitis media, the tympanic membrane becomes thickened, and the otoscopic landmarks become obliterated. Conductive hearing loss results from middle ear effusion, thickening of the tympanic membrane and middle ear mucosa, and destruction of the ossicles No characteristic pain or tendernessis evident, but lymphadenopathy in the high jugular chain occurs early. Multiple small perforations of the tympanic membrane may occur, with seropurulent drainage. The perforations quickly coalesce to cause loss of the tympanic membrane. Likewise, a myringotomy site in an intact tympanic membrane may enlarge quickly. The middle ear mucosa appears to be hyperemic with polypoid granulation. Osseous Involvement results in the sequestration of bone and the destruction of the inner ear, the facial nerve, or both. Destruction of the mastoidtipmay result in an asymptomatic, nontender Bezold abscess (a “cold” abscess). Rarely, tuberculosis can also manifest as primary tuberculous petrositis or as SNHL caused by chronic labyrinthitis and tuberculousmeningitis

13. The diagnosis of tuberculous involvement of the middle ear is usually delayed. The characteristic signs and symptoms include 1) multiple perforations of the tympanic membrane that quickly coalesce to form total tympanic membrane loss, 2) nontender cervical lymphadenopathy, 3) intractable otitis media with polypoid granulation, 4) bony sequestration. Otic capsule involvement with resultant loss of auditory and vestibular function may be the first symptom and indicates a process that differs from the more typical chronic otitis media. Definitive diagnosis is made by histopathologic examination of tissue from the middle ear or mastoid, which shows a granulomatous process with multinucleated giant cells (Langerhans cells; )and histologic demonstration of acid-fast organisms of tuberculosis. The accurate identification of the mycobacterial species and drug-resistant isolates by culture is still the gold standard, although culture is time consuming and takes several weeks. The process is facilitated by the use of several different types of nucleicacidamplification tests that have been approved by the U.S. Food and Drug Administration for rapid identification of M. tuberculosis

14. Multiple perforations of the tympanic membrane, exuberant polypoid granulation within the middle ear, and early loss of inner ear function also are seen in Wegener granulomatosis (WG) These two diseases are distinguished on the basis of skin tests for tuberculosis, histologic demonstration of acid-fast organisms of tuberculosis in granulation tissue, cultures of the middle ear, the presence of antineutrophil cytoplasmic antibodies (ANCAs) in WG, and the systemic manifestations of each process. The mainstay of management of tuberculosis of the middle ear and mastoid is the systemic use of standard antituberculous chemotherapy. Mastoid surgery may be required to remove sequestrated bone. Reconstructive surgery of the ossicles and tympanic membrane is feasible after the infection has been controlled.

15. I-GRANULOMATOUS AND INFECTIOUS DISEASES 3-WEGENER GRANULOMATOSIS a granulomatous inflammatory process with necrotizing vasculitis It primarily affects the upper and lower respiratory tracts and kidneys, but it can involve essentially any organ in the body. men = women mean age of onset is 40 years. Common presenting symptoms include headache, sinusitis, rhinorrhea, otitis media, fever, and arthralgia Upper airway and sinus involvement occurs in 75% to 90% of cases. Pulmonary manifestations include cough, pleuritic chest pain, hemoptysis, and nodular or cavitary infiltrates on chest radiography. Pulmonary manifestations occur in 65% to 85% of cases. Other manifestations include glomerulonephritis (60% to 75% of cases); eye involvement in the form of conjunctivitis, iritis, scleritis, or proptosis (15% to 50% of cases); and dermatologic findings of necrotic ulcerations, vesicles, or petechiae.

16. normochromic normocytic anemia; thrombocytosis; positive rheumatoid factor; and hyperglobulinemia, particularly of IgA. The ESR is almost always elevated. The discovery in 1985 of autoantibodies directed against the cytoplasmic constituents of neutrophils (antineutrophil cytoplasmic antibody [ANCA] and cytoplasmic ANCA [c-ANCA]) in patients with WG was a major advance in the diagnosis and understanding of WG. A positive ANCA test, especially proteinase 3–specific c-ANCA, is very helpful in establishing or supporting a diagnosis of WG. The specificity of positive c-ANCA testing in WG is greater than 95%; the sensitivity is variable and depends on the phase and type of WG. In more than 90% of patients with systemic and active WG, c-ANCA is positive; whereas in limited WG (e.g., ear or head and neck only or inactive disease), the sensitivity of c-ANCA is only 65% to 70%. In addition, the antibody titer parallels the activity of the disease, although data conflict about the value in using the titer as a guide for immunosuppressive therapy. The diagnosis of WG is made histologically by the presence of necrosis, granulomatous inflammation with multinucleated giant cells, vasculitis, and microabscess formation Small biopsy specimens, however, such as those obtained from the ear or upper airway, may lack all of the various diagnostic features. In such cases, a diagnosis of WG can be made on the basis of the clinical presentation, ANCA testing, and repeat biopsy specimens taken from the same or related sites.

17. The etiology and pathogenesis of WG are unknown. Infectious, genetic, and environmental risk factors and combinations thereof have been proposed. The evidence to date suggests that WG is a complex, immune-mediated disorder in which tissue injury results from the interplay of an initiating inflammatory event and a highly specific immune response. Part of this response consists of the production of ANCA , directed against antigens present within the primary granules of neutrophils and monocytes; these antibodies produce tissue damage by interacting with primed neutrophils and endothelial cells. The prognosis of WG  mortality rate of 82% before the era of immunosuppressive therapy current remission rate of more than 75% with appropriate medical therapy. Induction of remission is usually achieved with high doses of corticosteroids, cyclophosphamide, or methotrexate given for 3 to 6 months. Maintenance of remission is achieved with lower doses of corticosteroids and less toxic alternatives to cyclophosphamide, such as azathioprine, methotrexate, trimethoprim-sulfamethoxazole, or other drug combinations. Other therapies that have been used include leflunomide, mycophenolate mofetil, and the tumor necrosis factor inhibitors etanercept and infliximab.

18. Otologic Manifestations The middle ear and mastoid are the most common sites within the temporal bone that are involved in patients with WG, and WG may cause obstruction of the eustachian tube with resultant serous otitis media and conductive hearing loss Some patients also have purulent otitis media, and others may have frank granulomatous involvement of the middle ear and mastoid. The process can extend to involve the facial nerve and inner ear, and this usually manifests as rapidly progressive SNHL and loss of vestibular function. Otologic disease may be the sole and initial presenting feature in some patients with WG.

19. I-GRANULOMATOUS AND INFECTIOUS DISEASES 4-SARCOIDOSIS Sarcoidosis is a chronic multisystem disorder of unknown etiology characterized by the presence of noncaseating granulomas. It most frequently affects the lungs, although almost all body parts can be affected. The disease shows a femalepredominance and is 10 times more common in blacks than in whites. The onset of disease is usually during the third to fourth decade of life. Common presenting manifestations include bilateral hilar adenopathy on chest radiography, cough, and granulomatous skin rash. Other manifestations include iridocyclitis, keratoconjunctivitis, peripheral lymphadenopathy, hepatosplenomegaly, cardiac failure, myalgia, and arthralgia. Neurologic involvement includes central and peripheral manifestations, and the facial and optic nerves are the most commonly affected cranial nerves. Either peripheral mononeuritis or polyneuritis may be seen. Laboratory findings may include hilar adenopathy on chest radiography , hypercalcemia, and elevated serum angiotensin-converting enzyme.

20. The etiology and pathogenesis of sarcoidosis are unknown. The initial pulmonary lesion is an alveolitis characterized by the accumulation of CD4+ T cells; this is followed by development of noncaseating granulomas. The antigenic stimulus that initiates the disease process remains elusive. Several possible associations have been investigated that include mycobacteria, certain human leukocyte antigen complexes, abnormalities of T cells and the T-cell antigen receptor, and involvement of several different cytokines. Spontaneous resolution occurs in many patients. Corticosteroids are beneficial for patients with progressive symptoms or with ocular, cardiac, or central nervous system (CNS) involvement. For patients who cannot tolerate or do not respond to corticosteroids, alternative drugs include methotrexate, cyclophosphamide, azathioprine, chlorambucil, cyclosporine, chloroquine, pentoxifylline, and antagonists of human tumor necrosis factor-α, such as etanercept and infliximab.

21. Otologic Manifestations Otologic manifestations of sarcoidosis include SNHL, vestibular dysfunction, facial nerve paralysis, and occasionally granulomatous disease of the external or middle ear and mastoid. The facial nerve is the most commonly affected cranial nerve and is usually involved as part of the symptom complex of uveoparotid fever (Heerfordt syndrome) characterized by parotitis, uveitis, facial nerve paralysis, and mild pyrexia. The facial paralysis may be sudden in onset, is often bilateral, and may resolve spontaneously. Histopathology of the temporal bone in sarcoidosis has been reported in only one case; the main findings were perivascular lymphocytic infiltration and granulomatous inflammation that involved the cochlear, vestibular, and facial nerves within the internal auditory canal.

22. I-GRANULOMATOUS AND INFECTIOUS DISEASES 5-SYPHILIS Congenital and acquired syphilis may affect the middle ear in the late latent and tertiary forms. In the late latent form, the middle ear and mastoid may be affected by a rarefying osteitis with leukocytic infiltration of the ossicles and mastoid bone A similar but larger lesion of tertiary syphilis, the gumma, shows obliterative arteritis and central necrosis. A gumma of the ear canal or middle ear may result in perforation of the tympanic membrane and a granulomatous appearance of the middle ear mucosa. Definitive diagnosis of syphilis of the middle ear requires a positive serologic test and a histologic demonstration of Treponema pallidum Syphilitic involvement of the tympanic membrane and middle ear may mimic tuberculosis, and superinfection may result in chronic otitis media. Inner ear involvement may occur in the absence of macroscopic changes in the tympanic membrane or middle ear. The Hennebert sign, which is the induction of ocular deviation with positive or negative pressure in the external auditory canal, was believed to indicate a true fistula between the middle and inner ear as a result of rarefying osteitis of the otic capsule. The more probable cause is fibrous adhesions, however, between the stapes footplate and the membranous labyrinth as a result of endolymphatic hydrops. Combined antibiotic and corticosteroid therapy is beneficial for the management of SNHL.

23. I-GRANULOMATOUS AND INFECTIOUS DISEASES 6-LYME DISEASE Lyme disease is a multisystem inflammatory disorder that primarily affects the skin, nervous system, heart, and joints. It is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans by certain Ixodes ticks that are part of the Ixodes ricinus complex. The known primary reservoirs of the disease are white-footed mice and white-tailed deer. The disease was initially recognized in 1975 because of a clustering of patients with arthritis in Lyme, Connecticut, but it is now known that Lyme disease has been present for several decades in Europe, where it is called Bannwarth syndrome. Infection is usually acquired in the summer, and individuals of all ages and both sexes can be affected. Three clinical stages similar to the stages seen with cases of syphilis are recognized. 1-The first stage, early localized infection, begins 3 to 33 days after a tick bite with a characteristic skin lesion (erythema migrans). This lesion occurs in 60% to 80% of patients and may be accompanied by minor constitutional symptoms. 2- The second stage, early disseminated infection, occurs within days or weeks after inoculation and begins with hematogeneous dissemination of the organism from the site of inoculation. The symptoms, which mimic a systemic viral illness, include fever, migratory arthralgia, myalgia, headache, meningismus, generalized lymphadenopathy, malaise, fatigue, and secondary annular skin lesions.

24. After hematogenous spread, B. burgdorferi seems to be able to sequester itself in certain niches and can cause localized inflammation in the nervous system, heart, or joints. Neurologic involvement is manifested by meningitis, encephalitis, cerebrospinal fluid lymphocytosis, peripheral neuropathy, myelitis, or cranial neuropathy that includes facial nerve paralysis Cardiac manifestations include atrioventricular block or other arrhythmias, myocarditis, and pericarditis. Joint disease manifests as brief attacks of asymmetric oligoarticular arthritis, primarily in large joints and especially the knee. 3- The third stage, late or persistent infection, occurs more than 1 year after onset and can result in chronic, prolonged arthritis; chronic encephalomyelitis; chronic axonal peripheral polyradiculopathy; keratitis, similar to syphilis; acrodermatitis chronica atrophicans; and localized scleroderma-like lesions. A patient may experience one or all of the stages, and the infection may not become symptomatic until the second or third stage. Affected tissues show infiltration by lymphocytes and plasma cells. Mild vasculitis and hypercellular vascular occlusion can occur, but tissue necrosis generally does not. Granulomas, gummas, multinucleated giant cells, and fibrinoid necrosis have not been observed, in contrast to the findings in patients with syphilis.

25. In recent years, the complete genome of the spirochete has been sequenced, and animal models have been developed for studying the pathogenesis of Lyme disease using mice and primates. The animal models have shown that inflammatory innate immune responses are critical in the pathogenesis of the disease and that genetic factors may be important in determining the severity of some of the manifestations. The diagnosis of Lyme disease is usually based on the recognition of the characteristic clinical features, a history of exposure in an area where the disease is endemic, and detection of a specific antibody to B. burgdorferi by enzyme-linked immunosorbent assay and Western blotting. The antibody test must be interpreted properly using the criteria of the Centers for Disease Control and Prevention, because false-negative and false-positive results can occur. In addition, B. burgdorferi may cause asymptomatic infection, in which case the symptoms caused by another disease may be wrongly attributed to Lyme borreliosis. The spirochete is highly sensitive to doxycycline but only moderately so to penicillin. Other effective antibiotics include amoxicillin, erythromycin, cefuroxime, ceftriaxone, Steroids have been used for severe carditis and arthritis. Among patients managed early in the course of the disease, the specific antibody response usually disappears within months, and patients may become reinfected in the future. Among patients with late manifestations, such as arthritis, titers decline after successful management, but patients remain seropositive. Although two vaccines were developed and found to be effective in clinical trials, they are not currently being marketed.

26. Otologic Manifestations Facialnerveparalysis is the most common otologic manifestation, with a reported incidence of 3%to11% ; it may be bilateral in 25% of cases. This type of paralysis is seen in the secondstage of the disease, and it affects patients of all ages and both sexes. The onset is acute, the duration is weeks to a few months, and the return of function is spontaneous and is usually complete. There may be a history of preceding otalgia, ipsilateral facial pain, or paresthesias. Although other neurologic features of the second stage may be seen, facial nerve paralysis can occur as the sole neurologic abnormality. Antibiotics and steroids do not seem to influence the duration or outcome of facial paralysis, but they are recommended to treat concurrent symptoms and to prevent the more serious late complications. There is no role for surgery. The precise cause and histopathology of facial nerve palsy have not been elucidated. Histology from other involved peripheral nerves shows perineural and perivascular infiltration by lymphocytes and plasma cells. In chronic and severe neuropathies, demyelination and loss of nerve fibers similar to wallerian degeneration occur. It is unclear whether neural lesions result from an inflammatory response to the spirochete or represent an immune-mediated epiphenomenon. A well-documented otologic manifestation is an unusual skin lesion called a lymphocytoma, in which intensely red and violet nodules occur on the earlobe during the second stage of disease. The lesion consists of benign but hyperplastic lymphocytic follicles in the dermis. Auditory and vestibular manifestations such as SNHL, sudden hearing loss, positional vertigo, and Meniere-like symptoms have been described. More clinical data and temporal bone studies are needed to substantiate these preliminary observations.

27. I-GRANULOMATOUS AND INFECTIOUS DISEASES 7-MYCOTIC DISEASES Fungi are ubiquitous in the environment and are of low intrinsic virulence. Systemic invasive clinical disease reflects some defect in host defenses, such as diabetic ketoacidosis, chemotherapy for malignancy, corticosteroid therapy, or acquired immunodeficiency syndrome (AIDS). Aspergillosis, mucormycosis, candidiasis, cryptococcosis, coccidioidomycosis, and histoplasmosis are systemic mycoses that can cause disseminated disease and may involve the temporal bone. Diagnosis is made by biopsy and culture, and treatment consists of control of the underlying predisposing condition, surgical debridement of necrotic tissues, and systemic chemotherapy, usually with amphotericin B. Otologic Manifestations The middle ear and mastoid can be involved as a result of ascending infection along the eustachian tube and tensor tympani, which is often seen in mucormycosis , or through superinfection of existing chronic otitis media. Destruction of the middle ear cleft ensues, often with extension to the surrounding structures, including thrombosis or rupture of the internal carotid artery. Other routes of infection include hematogeneous embolic dissemination, which can result in multiple granulomas throughout the temporal bone, and through cryptococcal involvement of the CNS, which can cause invasion and degeneration of the nerve trunks in the internal auditory canal.

28. I-GRANULOMATOUS AND INFECTIOUS DISEASES 8-CYTOMEGALIC INCLUSION DISEASE Cytomegalic inclusion disease is caused by infection by the cytomegalovirus (CMV). Cochlear involvement may be congenital or reactivated from a latent state, particularly in immunocompromised patients. In the congenital form, infection may result in hepatic injury, brain injury, mental retardation, blindness, and deafness. The hearing loss caused by cytomegalic inclusion disease is variable and may be progressive or sudden in onset. Temporal bone histopathology of cytomegalic inclusion disease shows characteristic inclusions within the middle and inner ears that includes the nonsensory elements of both cochlear and vestibular systems

29. II-NEOPLASTIC DISEASES neoplasms of the temporal bone three neoplasms—multiple myeloma, leukemia, and metastatic 1-MULTIPLE MYELOMA Multiple myeloma is a malignancy of plasma cells derived from B lymphocytes, and its major feature is the demonstration of an abnormal monoclonal protein (M component) in blood, urine, or both. There is a slight male predominance, and the median age of onset is 60 years. Clinical manifestations are the result of multiple plasma cell tumors and consist of severe bone pain, pathologic fractures, failure of the bone marrow, renal failure, hypercalcemia, and recurrent infections. Laboratory findings include the demonstration of the M component on serum or urine electrophoresis, normochromic normocytic anemia, hypercalcemia, and elevated blood urea nitrogen levels. Typical radiographic findings include punchedout osteolytic lesions, which are particularly well seen on lateral skull radiography. Bone marrow aspirates show infiltration by plasma cells.

30. For decades, the mainstay of therapy has been the use of alkylating agents, such as melphalan and corticosteroids; with this regimen, the median survival is approximately 3 years. Important advances have been made more recently that have substantially altered therapy for patients with myeloma. These advances include the use of hematopoietic cell transplantation; improved supportive care measures, such as the use of bisphosphonates and erythropoietin; and novel agents such as thalidomide, lenalidomide, and bortezomib. Occasionally, only one plasma cell tumor (without marrow plasmacytosis) can be found. These lesions can occur in bone (solitary bone plasmacytoma) or soft tissue (extramedullary plasmacytoma), including the temporal bone. Both lesions can affect younger individuals, are associated with an M component in less than 30% of the cases, and have an indolent course with survival rates of 10 years or more. Local radiotherapy (40 Gy) is usually sufficient management. Periodic evaluation of serum and urine globulins and a skeletal radiographic survey should be performed to detect conversion to multiple myeloma.

31. Coronal computed tomography scan shows a large, destructive lytic lesion (arrows) of the clivus (CL), petrous temporal bone, middle ear, and jugular foramen area caused by multiple myeloma in a 72-year-old man. The presenting symptoms were facial nerve paralysisand otorrhea.

32. PF UN Coronal computed tomography scan with contrast enhancement and a soft tissue algorithm shows a slightly enhancing mass that has destroyed the mastoid bone and extends to the posterior fossa (PF) and upper neck (UN).

33. Otologic Manifestations The temporal bone is frequently involved in cases of multiple myeloma. Radiography may show rounded lytic lesions of the calvaria and temporal bone At a microscopic level, the marrow spaces of the petrous bone are commonly replaced by myeloma cells, and discrete lytic bone lesions may be seen in the otic capsule Symptoms referable to temporal bone involvement are usually overshadowed by manifestations of diffuse disease. Occasionally, these symptoms may be the presenting feature of myeloma, or they may be the only evidence of disease (plasmacytoma of the temporal bone). Symptoms are nonspecific and include hearing loss, tinnitus, vertigo, otalgia, and facial paralysis

34. II-NEOPLASTIC DISEASES 2-LEUKEMIA & LYMPHOMA Leukemic infiltrates may occur in the temporal bone. They are common in the submucosa of the pneumatized areas of the middle ear and mastoid, including the tympanic membrane and in the bone marrow of the petrous apex Secondary bacterial infection of the middle ear and mastoid often results from an immunocompromised state that is a result of either the disease itself or chemotherapy. Hemorrhage commonly occurs in association with infiltrates and can occur in the middle ear, mastoid, or inner ear. Clinical manifestations include middle ear effusion, acute and chronic suppuration in the middle ear and mastoid, thickening of the tympanic membrane, conductive hearing loss, SNHL (including sudden SNHL), vertigo, facial paralysis, and skin lesions in the auricle or external auditory canal. Granulocytic sarcoma, or chloroma, is a localized extramedullary tumor composed of immature myeloid cells. It is related to acute or chronic myelogenous leukemia, and its appearance may precede, coincide with, or follow the diagnosis of leukemia. Such a lesion can occur in the temporal bone, and otologic manifestations can constitute the initial presentation. Management is by local irradiation and systemic chemotherapy. LYMPHOMA Similar to leukemic infiltrates in the inner ear, both Hodgkin and non-Hodgkin lymphomas may result in hearing loss by either hemorrhagic or malignant infiltrative lesions of the middle and inner ear

35. II-NEOPLASTIC DISEASES 3-METASTATIC NEOPLASMS hematogeneous dissemination breast, lung, prostate, and skin The lesions are usually destructive and osteolytic however, some lesions, such as those from the prostate or breast, may be osteoblastic. The petrous apex and internal auditory canal seem to be sites of predilection for metastases, although any part of the temporal bone may be involved The otic capsule seems to be resistant to neoplastic invasion. Although otologic manifestations infrequently are the first evidence of malignant disease, more often they are preceded by other systemic symptoms. Involvement of the external canal, middle ear cleft, or eustachian tube may cause conductive hearing loss and pain; involvement of the otic capsule may produce SNHL, vertigo, and facial nerve paralysis. In meningeal carcinomatosis, rapidly progressive unilateral or bilateral SNHL is a common presenting symptom. Unilateral SNHL may mimic a cerebellopontine angle tumor, and bilateral SNHL may mimic immune-mediated inner ear disease. Diagnosis is made by cytology of the cerebrospinal fluid.

36. Axial computed tomography scan of an 82-year-old woman with metastatic breast adenocarcinoma showing a large lytic lesion (arrows) destroying the mastoid, squamosa, otic capsule, and labyrinth.

37. III-DISEASES OF THE BONE Paget disease, osteogenesis imperfecta, and osteopetrosis can sometimes mimic the clinical features of otosclerosis. 1-PAGET DISEASE Paget disease of bone (osteitis deformans) is a chronic and sometimes progressive disease of unknown etiology characterized by osteolytic and osteoblastic changes that mainly affect the axial skeleton. Geneticfactors play a role in the pathogenesis of Paget disease, which may be inherited in an autosomal dominant manner with high penetrance. Four susceptibility loci have been identified, one on chromosome 18, one on chromosome 6, and two on chromosome 5. Mutations in the SQSTM1 gene that encodes the sequestosome 1 protein have been found in some individuals. Viralinfection also seems to play a role in the etiology of Paget disease, based on electron microscopy and immunohistochemical studies. It is possible that the disease develops from a slow virus infection in susceptible individuals who have an underlying genetic predisposition. Paget disease affects 3% of the population aged 40 years and older and 11% of the population aged 80 years and older. Men are affected more commonly than women

38. . The onset of clinical manifestations is usually in the sixth decade of life and includes enlarging skull; progressive kyphosis; and deformities of the pelvis, femur, and tibia. Radiographic findings include a thickened skull table; patchy, ill defined densities of the skull; and poor definition of the cortical margins of the inner ear and internal auditory canal, particularly in the lytic phase of the disease. The bisphosphonates, which inhibit the resorption of bone, constitute the mainstay of medical therapy for symptomatic Paget disease. Other antipagetic drugs include calcitonin, mithramycin, ipriflavone, and gallium nitrate.

39. Lateral skull radiograph of a patient with Paget disease. (osteitis deformans) Findings include thickening of the skull table, multiple patchy densities, and platybasia.

40. Axial computed tomography scan of a 75-year-old man with Paget disease(osteitis deformans). Diffuse expansion of the skull table and involvement of both temporal bones with patchy demineralization is apparent.

41. Otologic Manifestations Clinical manifestations of Paget disease include hearing loss, tinnitus, and mild vestibular dysfunction. The facial nerve is spared. Hearing loss occurs in 5% to 44% of patients and may be sensorineural, mixed, or, rarely, conductive only. Most often, the loss is mixed, with a descending pattern for bone conduction and relatively flat air-conduction thresholds. Hearing losses are progressive and are greater than those of age-matched healthy subjects. Distinguishing features of Paget disease— compared with otosclerosis, which is the most common differential diagnosis—include a later age of onset, in the sixth decade; greater SNHL, with a descending pattern; enlarged calvaria; enlargement and tortuosity of the superficial temporal artery and its anterior branches; elevated serum alkaline phosphatase level; and radiographic evidence of pagetic changes in the temporal bones. None of the many published clinical and histologic reports have clearly identified a consistent pathologic basis for these hearing losses; specifically, the apparent conductive hearing loss is not caused by ossicular fixation, and SNHL is not caused by the compression of cochlear nerve fibers. Attempts at the surgical correction of conductive loss are generally not considered worthwhile. Monsell and colleagues73,74 reported a statistically significant correlation between the bone mineral density of the cochlear capsule (measured in vivo by quantitative computed tomography) and the high-frequency pure tone air conduction thresholds and the air-bone gap in patients with Paget disease of the skull. It is unclear whether this finding is only a marker of disease effect or a phenomenon closely related to the mechanism of hearing loss.

42. The histopathologic appearance of pagetic bone is variable and depends on the relative osteoclastic and osteoblastic activity. Typical findings include osteoclastic resorption of marrow containing bone with an increase in vascularity and formation of fibrous tissue. New bone formation occurs in an irregular manner and produces its typical mosaic pattern as a result of irregular and curved cement lines Pagetic bone changes occur in three phases: 1) an initial osteolytic phase, 2) a mixed or combined phase, and 3) an osteoblastic or “burnt out” phase. In the temporal bone, a fourth phase can be identified, which is the remodeling of inactive pagetic bone into normal-appearing lamellar bone. The disease usually begins in periosteal bone and extends to involve enchondral and endosteal bone.

43. III-DISEASES OF THE BONE 2-OSTEOGENESIS IMPERFECTA Osteogenesis imperfecta (OI), also known as van der Hoeve–de Kleyn syndrome, is a genetically determined disorder of the connective tissue characterized clinically by fragile bones that break with minor trauma. Approximately 80% to 90% of patients with OI have mutations of one of the two type 1 collagen genes, COL1A1 and COL1A2. Many hundreds of unique mutations of these two genes have been identified in individuals with OI. The older terms osteogenesis imperfecta congenita and osteogenesis imperfecta tarda have been replaced by a classification system that defines four types of OI based on clinical features, radiologic criteria, and mode of inheritance.

44. --OI type 1 has an autosomal-dominant mode of inheritance. It is the mildest form and is associated with blue sclerae, non deforming fractures, and normal stature. Hearing loss is common and occurs in 30% to 50% of cases. -- OI type 2 is the most severe form, in which multiple fractures occur in utero and often result in stillbirth. This type either is acquired as a sporadic new mutation or is inherited in an autosomal-recessive manner. -- OI type 3 is characterized by multiple fractures, progressive bone deformity during childhood and adolescence, and sclerae that are bluish at birth but white later in life. Hearing loss occurs in about 50% of individuals. The long bones may be slender and bowed with abrupt widening near the epiphyses. Kyphoscoliosis, pectus excavatum, weak joints, dental abnormalities, and wormian bone in the skull table are common The mode of inheritance varies; it may be autosomal dominant, autosomal recessive, or the result of a new mutation. --OI type 4 is a dominantly inherited form; it is similar to OI type 1 except that the sclerae are white (normal). Hearing loss is less common than it is with type 1 and occurs in 10% to 30% of cases. Management consists of the treatment of fractures, orthopedic surgery to correct deformities, use of orthotic devices, and physical and occupational therapy. Bisphosphonate therapy is being increasingly used, because these drugs are potent inhibitors of bone resorption and bone turnover. Other therapies under investigation include use of growth hormone and allogeneic bone marrow transplantation.

45. Lateral radiograph of the skull in a patient with osteogenesis imperfecta. Wormian bone is seen, particularly in the posterior table.

46. Radiograph of the arm of a patient with osteogenesis imperfecta. A pathologic fracture, demineralization of the humerus, and gross abnormalities of the elbow joint are evident.

47. Otologic Manifestations Conductive hearing loss and SNHL occur in patients with OI. Severe SNHL has been estimated to occur in approximately 40% of patients and has a high correlation with gray or white sclerae. Conductive hearing loss usually accompanies blue sclerae, which first becomes apparent by 20 to 25 years of age and then becomes severe enough to cause the patient to seek medical attention 15 to 20 years later. No relationship has been found between hearing loss and frequency or severity of fractures. Some patients with mild OI come to medical attention with conductive hearing loss similar to that seen with otosclerosis. Early age of onset of hearing loss, high compliance values on tympanometry, a history of fractures after minor trauma in childhood that ceased after puberty, a family history of OI, and blue sclerae are helpful diagnostic clues. The conductive loss reflects structural changes in the ossicles. Microfractures of the manubrium, fragility of the long process of the incus, and fracture or resorption of the crura of the stapes have been reported. The stapedial footplate is typically described as thick, soft, and chalklike or granular, and it is usually fixed. Rehabilitation can be accomplished by amplification or surgery. A stapedectomy can give results similar to those seen with otosclerosis, but the procedure is extremely delicate. Crimping the prosthesis around the incus may cause a pathologic fracture, and a platinum ribbon is preferred to stainless steel wire.

48. Histopathology of the temporal bone in cases of OI type 2 has shown deficient ossification of the endochondral layer of the otic capsule, which shows increased amounts of fibrous tissue with numerous blood vessels. The periosteal layer is often thin and deficient , and the stapes crura are often thin and incomplete. The otopathology in cases of OI type 2 is very similar if not identical to that seen in cases of otosclerosis. The abnormal bone involves the periosteal and endochondral layers of the otic capsule and may result in the fixation of the stapes footplate.

49. III-DISEASES OF THE BONE 3-FIBROUS DYSPLASIA Fibrous dysplasia is a benign, chronic, slowly progressive bone disorder of unknown etiology characterized by the replacement of normal bone with a variable amount of fibrous tissue and woven bone. It may occur as part of Albright syndrome—characterized by multiple bony lesions, abnormal pigmentation, endocrine dysfunction, and precocious puberty in girls—or it may exist alone in the monostotic or polyostotic form. The monostotic form is more common and usually occurs in the skull, ribs, proximal femur, or tibia. In the polyostotic form, skull lesions are seen in more than 50% of patients. Clinical manifestations of fibrous dysplasia include bony deformity, pathologic fracture, and cranial nerve palsies. The disease starts early in life, usually in childhood; the monostotic form may become quiescent at puberty, whereas the polyostotic form can continue to progress. Sarcomatous transformation can occur, and incidence is estimated at 0.4%. Laboratory findings include an elevated serum alkaline phosphatase level in 30% of patients with polyostotic fibrous dysplasia, with usually normal serum calcium and phosphorus levels. The typical radiographic findings include a radiolucent area with a well-defined smooth or scalloped edge and a ground-glass appearance. Areas of increased radiodensity may also be seen

50. The histopathology of fibrous dysplasia consists of the replacement of normal cancellous bone by a fibrous stroma arranged in a whorled pattern. A variable amount of irregularly arranged spicules of woven bone cause the ground-glass radiographic changes The lesion is composed of immature mesenchymal osteoblastic precursor cells. An activating mutation is present in the gene that encodes the α-subunit of stimulatory G protein. Elevated levels of cyclic adenosine monophosphate result that affect the transcription and expression of multiple downstream genes, which ultimately result in the pathologic lesion Treatment consists of bisphosphonate therapy and orthopedic surgery for correction of deformities and treatment of pathologic fractures