به نام خداوند دادار پاک - PowerPoint Presentation

Slide1

به نام خداوند دادار پاک پدیدآور آدم از آب و خاک

Otologic Manifestationsof Systemic Disease

1

Slide2

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

2

Slide3

3

Slide4

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 young adults, male predominance a solitary osteolytic lesion in the femora, pelvis, scapulae,vertebrae, ribs, mandible, maxilla, or skull, which includes thetemporal bone. The lesion may be asymptomatic, or it may cause pain, local swelling, or pathologic fracture. No systemic manifestations have been reported

4

Slide5

--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, lymph nodes, and visceraSystemic manifestations fever, anorexia, recurrentupper respiratory infections, anterior cervical lymphadenopathy,otitis media, and hepatosplenomegalyThe classic triad osteolytic skull lesions, exophthalmos as a result of orbital bone involvement, and diabetes insipidus secondary to pituitarydisease may be seen in 25% of patients

5

Slide6

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, andlow-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 andcytotoxic 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

6

Slide7

Otologic ManifestationsThe 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, hearing loss, 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.

7

Slide8

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 bonesThe 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.

8

Slide9

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

9

Slide10

Irregular lytic lesion in the mastoid bone (

arrows) of a 13-year-old boy with unifocal eosinophilic granuloma

10

Slide11

11

2-TUBERCULOSIS

I-GRANULOMATOUS AND INFECTIOUS DISEASES

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

Slide12

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 tenderness

is 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

mastoid

tip

may 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

tuberculous

meningitis

Slide13

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

nucleic

acid

amplification

tests

that have

been approved by the U.S. Food and Drug

Administration for

rapid identification of

M. tuberculosis

Slide14

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

.

Slide15

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

.

Slide16

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.

Slide17

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

.

Slide18

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.

Slide19

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

female

predominance 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

.

Slide20

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.

Slide21

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.

Slide22

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.

Slide23

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.

Slide24

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

.

Slide25

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.

Slide26

26

Otologic Manifestations

Facial

nerve

paralysis

is the most common otologic manifestation

, with

a reported incidence of

3%

to

11%

;

it may

be

bilateral

in 25%

of cases. This type of paralysis is seen in

the

second

stage

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.

Slide27

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.

Slide28

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

Slide29

29

II-NEOPLASTIC DISEASESneoplasms of the temporal bonethree 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.

Slide30

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.

Slide31

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 paralysis

and

otorrhea

.

Slide32

32

Coronal computed tomography scan with

contrast enhancement and a soft tissue algorithmshows a slightly enhancing mass that has destroyed the mastoid bone and extends to the posterior fossa (PF) and upper neck (UN).

UN

PF

Slide33

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

Slide34

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

Slide35

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.

Slide36

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.

Slide37

37

III-DISEASES OF THE BONE

Paget disease, osteogenesis imperfecta, and osteopetrosis can sometimes mimic the clinicalfeatures 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.

Genetic

factors 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.

Viral

infection 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

Slide38

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.

Slide39

39

Lateral skull radiograph of a patient with Paget disease

.

(

osteitis deformans

)

Findings include thickening of the skull table, multiple patchy densities,

and

platybasia

.

Slide40

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.

Slide41

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.

Slide42

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

.

Slide43

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

.

Slide44

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.

Slide45

45

Lateral radiograph of the skull in a patient with

osteogenesis imperfecta

.

Wormian bone

is seen, particularly in the posterior table.

Slide46

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.

Slide47

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.

Slide48

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.

Slide49

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

Slide50

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

Slide51

51

Lateral radiograph of the skull of a patient with

fibrous dysplasia showing lytic (L) and fibrous (F) phases of disease. Spicules of new bone are responsible for the ground-glass appearance of the fibrous phase.

F

L

Slide52

52

Coronal tomographic radiograph of a patient with

fibrous dysplasia. New bone formation causes a dense appearance of the involved left temporal bone.

L

Slide53

53

Fibrous dysplasia.

The

irregularly arranged spicules

of woven

bone in a fibrovascular stroma show a whorled pattern (×64).

Slide54

54

Otologic Manifestations

The temporal bone occasionally may be involved in cases

of fibrous

dysplasia, with about 100 cases reported to

date.

the

monostotic form occurred in 70%,

the

polyostotic



23

%

,

Albright

syndrome



7

%

All parts of the temporal bone can be involved, but the

process generally

begins as a painless, slowly progressive swelling

that involves

the mastoid or squama. Progressive narrowing of

the external

auditory canal with conductive hearing loss is the

most common

manifestation and occurs in about 80% of cases. This

narrowing may be mistaken for

exostoses

, but fibrous

dysplasia is

encountered during the second or third decade of life;

at surgery

, it is vascular with a characteristic soft, spongy, and

gritty consistency.

Entrapment of keratin debris medial to a

stenotic canal

can cause an external canal cholesteatoma.

Involvement of

the middle ear and ossicles or obstruction of the eustachian

tube also can cause conductive hearing loss.

Erosion

of the

fallopian canal

with facial nerve paralysis or erosion of the otic

capsule with SNHL and vertigo is seen occasionally.

An isolated lesion

of the mesotympanic bone can simulate a

glomus

tympanicum

tumor that can manifest as a reddish mass

behind an

intact tympanic membrane, with pulsatile tinnitus and

hearing loss.

Slide55

55

Management of fibrous dysplasia is symptomatic.

Operative procedures should be limited to biopsy and relief of functional deficits.

Stenosis of the external canal often requires surgical removal with canalplasty and meatoplasty. Restenosis as a result of regrowth of fibrous dysplasia occurs, and multiple procedures are sometimes needed.

Compared with simple canalplasty, a

postauricular canal-wall-down mastoidectomy

with wide canalplasty and skin grafting gives better results, with long term

canal patency.

Radiotherapy is contraindicated



an increased rate of malignant degeneration

Long-term follow-up is indicated because of the potential for facial nerve

involvement and for the progression of conductive hearing loss to profound SNHL

Slide56

56

III-DISEASES OF THE BONE

4-OSTEOPETROSES

Osteopetroses are rare genetic disorders characterized

by greatly

increased bone

density.

Osteopetroses result

from the

defective function of

osteoclasts

, which leads to a

failure of

normal bone resorption

, while normal bone formation

by osteoblasts

continues with deposition of excessive

mineralized osteoid

and cartilage.

Four

types of osteopetrosis have

been defined

, although patients with atypical symptoms are numerous

, which

suggests that additional types likely exist

.

1.

Malignant

osteopetrosis is an autosomal-

recessive

form

that

manifests

in

infancy

, is rapidly progressive, and has a high

mortality rate

. Many cases have been shown to be due to

mutations in

the gene that encodes for the TCIRG1 subunit of the vacuolar

proton pump within osteoclasts. The disease is

characterized by

the encroachment of bone marrow that leads to anemia

, thrombocytopenia

, hepatosplenomegaly, increased

susceptibility to

infection, and encroachment of the neural foramina,

which causes neural degeneration.

Optic

atrophy, facial paralysis

, SNHL

, hydrocephalus, and mental retardation are common

, and

death usually occurs during the first or second decade

of life.

The only effective treatment is bone marrow transplantation

.

Slide57

57

2.Another type of autosomal-

recessive

osteopetrosis is due to a mutation in the gene for cytoplasmic carbonic anhydrase II. This type is very rare (approximately 50 cases have been reported), and it is associated with distal renal tubular acidosis.

3. Autosomal-dominant

type 2 osteopetrosis, also known as

Albers- Schِnberg

disease and

marble bone disease

, is the

most

frequent

type

. It is associated with normal life expectancy and may

be asymptomatic

.

Many

cases have been shown to result

from mutations

in the

CLCN7 chloride-channel

gene.

Clinical

manifestations

include an increased incidence of

fractures (

osteopetrotic bone is fragile despite its solid appearance

); osteomyelitis

of the mandible from dental infection;

progressive enlargement

of the head and mandible; clubbing of

the long

bones; and cranial neuropathies such as progressive

optic atrophy

, trigeminal hypesthesia, recurrent facial paralysis,

and SNHL

. Patients may have syndactyly of the fingers or toes

and abnormal

fingernails; these abnormalities can aid the

physician in

making the clinical diagnosis

.

Radiographic

evaluation reveals

a great increase in the density of all bones

.

4. Autosomal-dominant

osteopetrosis type 1 is an extremely

rare

type

reported in only three families, and it seems to be

linked to

a locus on chromosome

11q12-13.

Patients with this

type of

osteopetrosis are often asymptomatic, but some have

pain and

hearing loss

.

This is the only type of osteopetrosis

not associated

with an increased rate of fractures.

Slide58

58

Otologic Manifestations

The endochondral layer of the otic capsule and ossicles in

the temporal

bones of infants and children with the

malignant recessive

form of osteopetrosis consist mainly of dense

calcified cartilage. The

mastoid is not pneumatized, and the

stapes persists

in fetal form

The

inner

ears appear

normal. Dehiscence of the tympanic segment of

the window

niche, has been a consistent finding

.

However,

no observable

nerve compression is evident. These children

often have

recurrent episodes of acute otitis media, serous

otitis media

, stenosis of the external auditory canal,

conductive hearing

loss or SNHL, and unilateral or bilateral facial

nerve paralysis.

In the more benign adult form (autosomal-dominant type

2 osteopetrosis

), the temporal bone is markedly sclerotic

with obliteration

of the mastoid air cells and a narrowing of

the eustachian

tube and the external and internal auditory canals.

Exostotic overgrowth of the periosteal bone surrounding

the tympanic

cavity can occur

,

with ankylosis of

the ossicles

and obliteration of the oval and round window niches

These changes explain the common finding

of conductive

hearing loss. SNHL also occurs, but the inner

ears appear

normal. Narrowing of the eustachian tube

predisposes a

patient to serous otitis

media.

Recurrent acute facial

nerve paralysis

that is similar to Bell palsy, involving one or both sides

, is

a frequent manifestation. The tendency is toward progressive

residual weakness with each episode. Radiographic

studies should

be performed in any child or

young

adult with

recurrent facial

nerve paralysis to determine the possibility of osteopetrosis.

Total decompression of the facial nerve has been

advocated to

ameliorate recurrent palsies

Slide59

59

Recessive osteopetrosis of the temporal bone of

a 15-month-old boy. The endochondral layer of the otic capsule and stapes is composed of calcified cartilage (×12.3).

Higher magnification of the temporal

bone The calcified cartilage (CC) of endochondral bone appears as densely staining, round-to-ovoid profiles (×396).

CC

Slide60

60

Osseous obliteration of the round window niche (RWN

) .

Fluid is apparent in the niche adjacent to the round window membrane (RWM; ×18).

Osteopetrosis in a 30-year-old man shows overgrowth of dense lamellar bone around the epitympanum with jamming of the malleus (M) and incus (I). The facial nerve canal (FC) is narrowed (×9). A, antrum; LSCC, lateral semicircular canal.

FC

M

I

A

LSCC

RWM

RWN

Slide61

61

III-DISEASES OF THE BONE

5-OSTEITIS

FIBROSA CYSTICA

Osteitis fibrosa cystica, also known as

von Recklinghausen disease

,

is

a bone lesion caused by

excess parathyroid hormone

, and

it is

characterized in classic cases by

osteoclastic bone resorption

, marrow

fibrosis, bone cysts, bone pain, and fractures

.

In

most cases

, it is caused by primary hyperparathyroidism, usually

because of an adenoma.

Other

manifestations relate to

hypercalcemia and

hypercalciuria

.

Although the temporal bone

can be

affected in this

disorder,

it is very rare in clinical practice.

The otic capsule is replaced by abnormal bone

composed of

loosely arranged trabeculae of varying sizes and shapes

interspersed with

marrow spaces that contain fibrous tissue.

SNHL has

been attributed to osteitis fibrosa that involves the temporal

bone.

Slide62

62

IV--STORAGE

AND

METABOLIC DISEASES

1-MUCOPOLYSACCHARIDOSES

The mucopolysaccharidoses (MPS) are a group of

diseases caused

by an inherited deficiency of one of several

lysosomal enzymes

that

degrade mucopolysaccharides

. As a result,

undergraded mucopolysaccharides

accumulate intracellularly, which

gives rise to large cells with vacuolated cytoplasm.

Ten enzyme

deficiencies

have been identified to date and are classified into

seven types or syndromes

.

All are transmitted as

autosomal recessive

traits

except for

Hunter

syndrome (MPS 2), which

is

X-linked

recessive

.

Diagnosis

is made either by an assay of

the specific

enzyme in plasma or serum or by tissue culture

using fibroblasts

or leukocytes

.

Management is mainly supportive

and symptomatic

; however,

mucopolysaccharidoses

are

potentially amenable

to enzyme replacement therapy and to

procedures such

as bone marrow transplantation or gene

transfer.

1-Hurler

syndrome (MPS 1

) is caused by a deficiency

of l-iduronidase

that leads to the accumulation of heparan

sulfate and

dermatan sulfate

.

Clinical manifestations include

corneal clouding

, abnormal facies, hepatosplenomegaly, mental retardation

, dysostosis

multiplex, joint stiffness, and hernias.

Radiographic features

include a broadening and shortening

of long

bones; hypoplasia and fractures of the

lumbar

vertebrae

, causing

kyphosis; and enlargement of the sella turcica.

Death usually

occurs during the first decade of life.

Slide63

63

2-Hunter

syndrome (MPS 2)

results from a deficiency

of iduronate-2-sulfatase

, which leads to an accumulation

of heparan

sulfate and dermatan sulfate.

The

syndrome is

similar to

Hurler syndrome, but corneal clouding is not seen.

Survival to

adulthood may occur

.

3-Morquio

syndrome (MPS 4)

is attributable to a

deficiency of

N-acetylgalactosamine-6-sulfatase or of

β-galactosidase

,

which results

in excessive urinary excretion of keratan sulfate

.

Clinical manifestations

include spondyloepiphyseal dysplasia.

Spinal cord

compression caused by hypoplasia of the odontoid

process and

cervical dislocation are common and may be the cause

of death.

OTOLOGIC Manifestations

Hearing loss in MPS is usually conductive and sensorineural.

The conductive component is attributable to serous

otitis media

as a result of dysfunction of the eustachian tube

and chronic

thickening of the mucosa of the middle ear

Unresorbed mesenchyme has been described in

the middle

ear and mastoid in

Hurler

syndrome,

and large

cells with

vacuolated cytoplasm have been described in the

middle ear

mucosa in both

Hunter

and

Hurler

syndromes.

The cause

of SNHL is unknown, but it has been attributed to abnormal

metabolism within neural element

Slide64

64

Hunter syndrome in a 24-year-old man. The middle

ear contains an effusion (EF) as a result of eustachian tube dysfunction. The submucosa (SM) is thickened, and the posterior mesotympanum (PM) contains unresorbed mesenchymal tissue (×11).

PM

EF

SM

Slide65

65

2-GoutGout is a metabolic disease that results from the deposition of crystals of monosodium urate within joint spaces and cutaneous structures. The crystals stimulate production of interleukin-1 and other cytokines by monocytes and macrophages, which leads to inflammation and tissue damage.Patients with gout invariably have hyperuricemia (serum urate level >7 mg/dL). Genetic factors influence the renal clearance of uric acid and may be involved in the familial incidence of hyperuricemia and gout. More recent studies have implicated loci on the X chromosome and on chromosome 16 in the pathogenesis of hyperuricemia. Other risk factors for gout include alcohol use, exposure to lead, use of diuretics, hypertension, and renal insufficiency.

IV--STORAGE AND METABOLIC DISEASES

Slide66

66

The clinical manifestations of gout include

acute gouty arthritis

, aggregates of

crystal in connective tissue (tophi),

urate

urolithiasis

, and, rarely, gouty

nephropathy

.

Laboratory abnormalities



hyperuricemia

,

leukocytosis

, and an elevated

ESR

The diagnosis of gout depends on the identification of urate crystals within joint fluid or within tophi under polarized light.

The treatment of acute gouty arthritis includes bed

rest

, nonsteroidal

antiinflammatory

agents, and

colchicine

.

Uricosuric drugs such as probenecid

are useful for patients with hyperuricemia as a result of the decreased renal clearance of uric acid.

Xanthine oxidase

inhibitors such as

allopurinol

are useful if excess production of uric acid is the basis of the hyperuricemia.

Otologic Manifestations

Tophaceous deposits

can occur in multiple areas in the head and neck.

The

helical rim of the pinna

is the classic site of involvement.

Such tophi are usually

asymptomatic

and do not require any

treatment

Slide67

67

IV--STORAGE AND METABOLIC DISEASES

3-OCHRONOSIS

a

rare disease

caused by an

inherited lack of

the

enzyme

homogentisic acid

oxidase

The

presence of

homogentisic acid

in urine is called

alkaptonuria

The

result of this

inborn

error

of metabolism is the deposition of a

dark pigment

in

tissues that are

rich in collagen

.

Patients

often come to

medical attention

with

symptoms and signs during the

third decade

of life

.

Manifestations

include ochronotic

arthropathy

,

ocular

and

cutaneous

pigmentation, obstruction of the

genitourinary

tract by

ochronotic calculi, and

cardiovascular

manifestations as

a result

of ochronosis that affects the aortic valve.

There

is

no effective

management

or cure for the condition, and treatment

is based on

symptomatic

therapy.

Otologic Manifestations

Ochronosis has manifestations in the

external ear

, and

cartilage

is

a site of predilection for the deposition of the pigment

of ochronosis

.

Blue

or mottled-brown macules can appear on

the pinna

and in other areas of the head and neck, including

the nose

, buccal mucosa, tonsils, pharynx, larynx, and esophagus.

Slide68

68

Ochronosis

Slide69

69

V-COLLAGEN VASCULAR AND AUTOIMMUNE DISEASES

The ear may be a target organ in

-several

systemic (

non–organ

specific

) diseases

thought to be autoimmune in nature (e.g

., polyarteritis

nodosa, relapsing polychondritis, Cogan syndrome),

-or

it may be the sole target of an

immune-mediated (

organ-specific

) inner ear process that causes

progressive SNHL

with or without vestibular

dysfunction( described

by

McCabe,,

proposed

by

Lehnhardt in

1958

)

Histopathologic findings

in the

temporal bone in both groups of disorders are

similar

and include

destruction and degeneration of the inner ear tissues;

scattered infiltrates of lymphocytes, plasma cells, and macrophages;

focal or diffuse proliferation of fibrous tissue and bone

;

and

a variable degree of endolymphatic

hydrops.

Slide70

70

V-COLLAGEN VASCULAR AND AUTOIMMUNE DISEASES

1-MULTIPLE SCLEROSIS

a

demyelinating disease of the

brain and

spinal

cord

Most

investigators believe that MS is

an immune-mediated

disorder.

The

incidence of MS

is 2 to

150 per

100,000

population with a

female

predominance.

Although the

constellation of symptoms is vast, the principal

effects related

to the ear are

hearing

loss, particularly loss of word recognition ability

,

and

vestibular

symptoms

It

is not

clear whether

these symptoms can be attributed to peripheral or

central auditory and vestibular neural

pathways.

--abnormal auditory brainstem

potentials in MS that imply interference with the

ability to make intraaural time discriminations within the

auditory CNS.

--a 48-year old

woman with MS

in which the temporal bones and

CNS pathology

were available for study.

Although the patient

had no

documented auditory symptoms, she did have a

well documented history

of vertigo

.

The inner ear structures,

both auditory

and vestibular, were normal, and the vestibular

symptomatology was

attributed to plaques within the vestibular

pathways in

the CNS

Slide71

71

V-COLLAGEN VASCULAR AND AUTOIMMUNE DISEASES

2-SUSAC

SYNDROME

a

microangiopathy

that affects

the

brain

,

retina

, and

cochlea

Symptoms include

encephalopathy

,

visual defects

as a result of branch retinal

artery occlusion, and

SNHL

.

The pattern of

hearing

loss

varies

considerably and may be

rapid

or

progressive

; a

low-tone audiometric

predominance

is common.

Magnetic resonance imaging

shows supratentorial lesions of the white matter

and involvement of the corpus callosum

.

Treatment

includes

immunosuppressive

therapy and,

if

indicated,

cochlear implantation

.

Temporal

bone findings in

a 51-yearold woman

, had bilateral low-frequency SNHL. Findings

on magnetic

resonance imaging were consistent with Susac

syndrome:

Temporal bone histopathology consisted of

widespread degeneration

within the apical portion of both cochleae

and included

the inner and outer hair cells, tectorial membranes

, stria

vascularis, spiral ligament, and spiral limbus.

Capillary occlusion

within the stria vascularis was also evident, and in

contrast, the cochlear neurons were normal in appearance

.

No evidence

of endolymphatic hydrops was found, and the vestibular

end organs were normal.

Slide72

72

VI-IMMUNODEFICIENCY

DISORDERS

Occasionally

, otologic manifestations

may constitute

the presenting feature of the disease

.

1-PRIMARY

OR

CONGENITAL IMMUNODEFICIENCY DISORDERS

Primary or congenital immunodeficiency disorders

constitute a

diverse group of conditions that can be subdivided into

four broad

categories.

1-Humoral

immunodeficiency disorders

are

characterized

by

the inability to produce antigen-specific antibodies.

Patients commonly have recurrent and chronic

respiratory tract

infections owing to high-grade extracellular bacteria

, such

as

Haemophilus influenzae, Streptococcus pneumoniae,

and S

. pyogenes

.

Diagnosis is based on the analysis of

immunoglobulin

subtypes

and the assessment of specific antibody production.

Management is symptomatic with appropriate

antibiotics

and

replacement therapy with

immune human serum globulin

.

Individual syndromes within the group are

classified according

to the type of immunoglobulin (Ig) deficiency,

the mode

of genetic transmission, and the specific clinical features

, including

X-linked

infantile

agammaglobulinemia (

Bruton),

autosomal-recessive

agammaglobulinemia

,

acquired agammaglobulinemia

(common variable immunodeficiency),

X-linked immunodeficiency with hyper-IgM,

and

selective

IgA deficiency

Slide73

73

2-Cellular

immunodeficiency disorders

exhibit partial or

severe

deficiencies

in the function of T lymphocytes

.

Patients

with these

disorders typically have recurrent infections owing

to

intracellular

, low-grade, opportunistic pathogens

that

include

viruses

,

fungi

,

protozoa

, and

some

bacteria

.

Diagnosis

is

based on

quantitative and qualitative tests of T-cell function, and an

associated deficiency of antibody production is often present.

Syndromes include

thymic

hypoplasia (DiGeorge syndrome),

Wiskott-Aldrich syndrome,

ataxia-telangiectasia

,

chronic mucocutaneous candidiasis

,

hyperimmunoglobulinemia

E ( Job syndrome),

and severe combined immunodeficiency

.

3-Disorders of phagocyte function

are primarily disorders of neutrophils

that leave patients vulnerable to pyogenic bacterial

or fungal

infections of varying severity and chronicity

.

This

group includes

neutropenia, which may be inherited or acquired

;

if severe

, it can cause fulminant sepsis,

chemotactic

defects

that result

in pyogenic respiratory infections,

and

microbicidal

disorders such

as chronic granulomatous disease and Chediak-

Higashi syndrome.

Therapy

includes antibiotics,

neutrophil transfusions

, and bone marrow transplantation

.

Slide74

74

4-Complement system defects

include deficiencies of the individual

components or of the regulatory proteins, and all complement defects are inherited (generally autosomal recessive).

Clinical features vary with the type of defect and include

recurrent

Neisseria infections (C5, C6, C7, and C9 deficiency),

Recurrent

staphylococcal infections (C3b inactivator deficiency),

Lupus like syndromes (C1, C4, and C2 deficiency),

and angioedema (C1 esterase inhibitor deficiency).

Management of these is symptomatic and supportive.

Major advances have been made in the understanding of the genetic basis and molecular mechanisms of immunodeficiency disorders. As a result, most of the more than 100 primary immunodeficiency diseases can be diagnosed by molecular

techniques. These molecular approaches have also resulted in significant insight into the pathophysiology of the various conditions, which has permitted early diagnosis of many of these conditions by neonatal screening of umbilical cord blood. The

immunodeficiency syndromes have also played a major role in

the development of human gene therapy, which is being

actively pursued

in many centers

.

Slide75

75

Otologic Manifestations

Humoral immune defects result in recurrent and persistent acute and serous otitis media.

Chronic suppurative otitis media and its attendant complications may develop and is often refractory to medical and surgical therapy

A subgroup consists of children with selective

IgG subclass 2 deficiency

, who have been shown to be susceptible to recurrent episodes of otitis media.

DiGeorge

syndrome, T-cell deficiency as a result of thymic hypoplasia, can

manifest varying degrees of

anomalies of the external, middle, and inner ears

with conductive, sensorineural, or mixed hearing losses ; a high incidence of

Mondini

dysplasia is also seen in these ears.

Recurrent episodes of acute and chronic otitis media have also been described with neutrophil chemotactic defects,

microbicidal disorders (chronic granulomatous disease),

and complement system defects.

Slide76

76

VI-IMMUNODEFICIENCY DISORDERS

2-ACQUIRED IMMUNODEFICIENCY SYNDROME

Acquired immunodeficiency syndrome (AIDS), which was

first recognized

in 1981, is caused by HIV, a lymphotropic

virus that

primarily attacks T-helper lymphocytes and renders

the patient

susceptible to numerous opportunistic infections

Otologic

Manifestations

--Otologic

manifestations are

infrequent

in

children

,



serous

otitis media

is

common

When otologic disease does occur, the microbiology is

similar to

that of non-AIDS patients, with the addition of

unusual opportunistic

organisms, such as protozoa, fungi, viruses,

and mycobacteria

.

Middle ear and mastoid manifestations include acute

otitis media

, acute mastoiditis, serous otitis media, and bullous myringitis;

the severity of these infections varies and depends

on the

immune status of the patient

.

External ear disease such

as otitis

externa and Kaposi sarcoma can also occur. Tissue

diagnosis by

biopsy or tympanocentesis is indicated to identify the

causative agent before initiating therapy

.

Slide77

77

Pneumocystis jiroveci

is an unusual opportunistic protozoan

that is a common cause of middle ear and external ear disease in patients with AIDS

Subcutaneous masses

in the external canal or

aural polyps

that arise from the canal, the tympanic membrane, or the mesotympanum can result in conductive

hearing loss, otorrhea, or otalgia.

Presumed routes of infection include

hematogenous

spread from another source (e.g., pulmonary),

ascending

infection through the eustachian tube from pharyngeal colonization, or

airborne

transmission of the aerosolized organism directly to the external canal.

A biopsy specimen shows the characteristic organism, and the infection responds to treatment with oral

trimethoprim sulfamethoxazole

Otologic disease that results from

P. jiroveci

may be the initial and only presenting symptom of AIDS.

Slide78

78

Inner ear symptoms can occur such as vertigo, tinnitus, and SNHL that includes fluctuating and sudden hearing loss.

SNHL is ascribed to various causes that include otosyphilis, cryptococcal meningitis, tuberculous meningitis, CNS toxoplasmosis, and ototoxic medication.

HIV is neurotropic and may itself be the primary cause of SNHL, and the facial nerve can be involved by herpes zoster (Ramsay Hunt syndrome).

In a study of 49 temporal bones from 25 patients with AIDS,

-low-grade otitis media in 60% of cases,

-

severe otitis media in 20%,

-

CMV inclusion-bearing cells in the inner and middle ears in 24%, labyrinthine cryptococcosis in 8%,

and Kaposi sarcoma deposits in the eighth cranial nerve in 4%.

Slide79

79

GENETICALLY

DETERMINED DEFECTS

Numerous syndromic disorders secondary to genetic defects

may have otologic manifestations that consist of hearing loss or

vestibular dysfunction or both

.

Examples include

syndromes caused

by mutations in single genes (autosomal or sex linked

), mutations

in mitochondrial genes, or chromosomal abnormalities.

Such disorders are beyond the scope of this chapter, and

the reader is referred to Chapter 147 or other

sources.