Otologic Manifestations of Systemic Disease: Includes Autoimmune Inner Ear Disease

Otologic Manifestations of Systemic Disease: Includes Autoimmune Inner Ear Disease

Arnaud F. Bewley

Michael J. Ruckenstein

Numerous systemic diseases can affect the ear, causing a variety of otologic complaints including hearing loss, vestibular dysfunction, and facial nerve paresis. These diseases span a broad differential including infectious, granulomatous, autoimmune, bone, and metabolic etiologies (Table 156.1). Prior to progressing to systemic involvement, many can initially present as a process isolated to the ear. It is therefore critical that the otolaryngologist be aware of this broad differential when evaluating any otologic complaint. This chapter provides a systematic review of this differential, discussing the most pertinent examples of each etiology. The topic of autoimmune disease includes a discussion of autoimmune inner ear disease (AIED), a rare cause of sensorineural hearing loss (SNHL), given that what we know about the pathophysiology of this disease derives largely from our knowledge of how systemic autoimmune diseases affect the ear.


Infectious diseases are the most common type of systemic disease to manifest otologic pathology. Pathogens may infect the inner ear and auditory pathways in utero, resulting in congenital syndromes that often include deafness, or infection may be acquired after birth. As the fluids of the inner ear are not easily accessible for sampling, the implication of viral pathogens as the causes of otologic disease has often depended on circumstantial evidence, including an associated viral illness, like an upper respiratory infection, or demonstration of seroconversion during the time of hearing loss. In other cases, more direct evidence exists such as with CMV infection, where DNA has been amplified using PCR from perilymph obtained during cochlear implantation in children previously diagnosed with congenital infection (1).


Cytomegalovirus (CMV) is a large double-stranded DNA virus belonging to the herpes virus family. Its name derives from the typical appearance of infected tissues, containing massively enlarged cytomegalic inclusion cells. CMV is the most common congenital infection in the world. One percent of babies born in the United States are infected; the likely route of infection is transplacental. Of these babies, 10% will exhibit symptomatic infection, or cytomegalic inclusion disease, almost exclusively when primary maternal infection occurs during pregnancy (2). Of those babies that survive the neonatal period, the majority will have severe neurologic deficits and a severe bilateral SNHL. Possibly more significant, from an epidemiologic point of view, is hearing loss that develops in those children with apparently asymptomatic congenital CMV infection; between 7% and 15% of these infants will go on to develop SNHL. Most cases will be mild, but up to a quarter will be severe (3). Hearing loss may be unilateral or bilateral and may develop months or years after birth and be missed on routine audiometric screening. It is thought that asymptomatic CMV infection causes 20% to 30% of congenital hearing loss. In the healthy adult, CMV infection is usually asymptomatic or may cause a mononucleosis-like syndrome. In human immunodeficiency virus (HIV)-infected or transplant patients, severe multisystemic disease may ensue, but hearing loss is not common.


Rubella is a member of the Togaviridae family. Primary maternal infection during the first trimester of pregnancy may result in congenital rubella syndrome. SNHL is the most common manifestation of this disease, seen in up to 60% of affected infants. Hearing loss may be bilateral or unilateral, may manifest as late as the second year of life, and may be the only sign of infection. Other features are ocular malformations, including cataract and retinopathy; cardiac malformations; and central nervous system (CNS) disease. Postnatal infection produces German measles, a mild viral illness (4).


Infectious diseases

Viral infection







Bacterial infection


Lyme disease

Granulomatous disease

Langerhans histiocytosis


Wegener granulomatosis

Autoimmune disease

Cogan’s syndrome

Polyarteritis nodosa

Relapsing polychondritis

Rheumatoid arthritis

Diseases of bone

Paget disease

Osteogenesis imperfecta

Fibrous dysplasia


Metabolic disorders



Varicella-zoster virus (VZV) is a herpes virus that results in varicella or chickenpox with primary infection. Once the primary infection is cleared, VZV remains dormant in the dorsal root ganglia. Reactivation of the virus, often during periods of suppressed cellular immunity, results in shingles, or a dermatomal vesicular eruption. Reactivation of VZV in the geniculate ganglion results in Ramsay-Hunt syndrome, or herpes zoster oticus. Involvement of the facial nerve results in the classical presentation of deep otalgia, vesicular eruptions on the external ear and tympanic membrane, and facial palsy. Extension of the inflammatory process to involve the vestibulocochlear nerve may result in SNHL and vertigo.

Mumps and Measles

The mumps and measles viruses are members of the Paramyxoviridae family. Infection with this virus is rare in the developed world due to widespread use of vaccination, though it is still common worldwide. Mumps infection commonly presents with unilateral or bilateral parotitis and orchitis in males. The classic presentation of measles (rubeola) involves cough, coryza, conjunctivitis, white oral mucosal lesions known as Koplik spots, and a maculopapular rash. SNHL with mumps is uncommon, affecting less than 0.05% of patients, and tends to be unilateral (5). Similarly, hearing loss is uncommon in measles infection, seen in approximately 0.1% of patients.


HIV infection is associated with a significant incidence of SNHL, though this relationship is not fully understood. The etiology is likely variable and includes a high incidence of middle-ear disease, opportunistic infections and malignancies of the CNS, viral labyrinthitis and neuritis, and ototoxicity from medications used to treat HIV infection and its complications (6).

Bacterial Infection

Most bacterial infections involving the inner ear represent extension of inflammation or infection from the middle ear or CNS. Acute otitis media can produce a sterile serous labyrinthitis secondary to the passage of bacterial toxins and inflammatory mediators into the inner ear fluids, likely through the round window or a dehiscent lateral semicircular canal in patients with chronic middle-ear disease and cholesteatoma. This typically causes a mild high-frequency hearing loss. Entrance of bacteria into the inner ear will lead to a suppurative labyrinthitis, which is heralded by severe hearing loss, vertigo, and vegetative symptoms.

Similarly, in patients with meningitis, bacteria may invade the labyrinth via the internal auditory canal or the cochlear aqueduct. SNHL is a common complication of meningitis, particularly in children. Up to a third of patients with bacterial meningitis sustain some loss of hearing. The hearing loss is typically bilateral and stable, though it may be unilateral and progressive or fluctuating. Male sex, CT scan evidence of elevated intracranial pressure, nuchal rigidity, low cerebrospinal fluid (CSF) glucose levels, and Streptococcus pneumoniae as the infective agent all are associated with an increased incidence of postmeningitic SNHL.


Syphilis was historically a common cause of otologic dysfunction though this late manifestation of the disease is uncommon today in the developed world. Syphilis is caused by infection with Treponema pallidum, which may be transmitted transplacentally (congenital syphilis) or through sexual contact (acquired syphilis). Though the incidence of syphilis peaked in the United States in the 1940s and has since declined, there has recently been an increase in the incidence among male homosexuals and patients with HIV (7,8). Syphilis is characterized by classic symptomatic stages interspersed with periods lacking significant symptoms. Primary syphilis is typically seen in the acquired form and is characterized by the presence of a chancre (a painless, nonpurulent, and indurated ulcer
in the region of sexual contact), which usually appears 3 weeks after initial infection. Although usually solitary, multiple ulcers may be seen in HIV-infected patients (7); however, chancres may go unnoticed and may only be seen in a third of cases (9). Symptoms can last from 3 to 90 days, but often go unnoticed (10). Secondary syphilis occurs weeks after the chancre has healed and is characterized by a variety of mucosal and cutaneous lesions that appear 2 to 12 weeks after initial infection (it may overlap the primary stage in up to 75% of HIV-infected patients) as well as the presence of constitutional symptoms such as fever and malaise. Asymptomatic meningitis may occur in up to 40% of patients (10), although associated sudden progressive bilateral hearing loss and vertigo are rare (11). Other organ systems may be involved, including the liver, kidney, eyes, and joints. The latent phase follows, which is characterized by a lengthy period free of symptoms. Tertiary syphilis, which is similar to late congenital syphilis, manifests years after initial infection. It is characterized by cardiovascular, gummatous, and neurologic involvement. Approximately 15% to 40% of untreated patients will progress to the third stage (7). Neurosyphilis is composed of meningovascular and parenchymal lesions that can lead to demyelination (tabes dorsalis), motor weakness, and sensory loss.

The diagnosis of syphilis depends on clinical findings, histologic examination of lesions, and serologic testing for syphilis. The Venereal Disease Research Laboratory screening test and rapid plasma reagin are useful screening tests, but lack sufficient sensitivity for both early and late syphilis (10). Treponemal tests, such as the fluorescent treponemal antibody absorption (FTA-ABS) test or a microhemagglutination test for T. pallidum, have higher sensitivity and specificity, and are often required for diagnosis. In fact, routine serologic testing for otosyphilis is recommended in all cases of idiopathic progressive SNHL (12). In addition, the diagnosis of neurosyphilis may require testing of CSF (10).

The otologic manifestation of syphilis presents as both hearing and vestibular dysfunction. Sensorineural hearing is very common from both in congenital and the later stages of acquired syphilis. It can be present in up to 40% of patients with congenital syphilis and up to 80% to 90% of patients with neurosyphilis (13). In addition, many patients present with vestibular dysfunction similar to that seen with Ménière disease (14). In fact, it has been reported to be present in up to 7% on patients thought to have Ménière disease (11). Left untreated, however, otogenic syphilis has a more aggressive course than Ménière disease, commonly involving both ears and leading to profound deafness. Physical exam reveals signs consistent with SNHL and peripheral vestibular loss. Hennebert sign (vertigo and nystagmus induced with air pressure to the middle ear) and Tullio phenomenon (vertigo and nystagmus caused by loud noise) may be associated with tertiary syphilis.

The changes in the inner ear resulting from syphilis have been well described. The otic capsule may be involved during the secondary and/or tertiary stages of infection. Involvement manifests as osteitis of the otic capsule bone. Inflammation is mediated by mononuclear cells and results in patchy bone reabsorption; these spaces are subsequently filled with fatty marrow and loose connective tissue (15). It is accompanied by an obliterative endarteritis typical of syphilitic infection. In severe cases, gumma (lymphocytic infiltrates, vascular occlusion, and central necrosis) may be noted in the otic capsule. In addition, degeneration of the labyrinthine membrane, endolymphatic hydrops, and fibrosis have been described (16). The peripheral vestibular system may also be involved during the second stage of infection, in which both the VIII cranial nerve and labyrinth are involved in fulminant meningoneurolabyrinthitis.

Penicillin-based antibiotics (or an alternate if allergic) are the treatment of choice, with duration varied by stage of disease. The use of corticosteroids in the treatment of otogenic syphilis is controversial (11,17,18,19,20). The prognosis for hearing loss in otogenic syphilis is poor, with hearing improvement seen in less than one-third of treated patients (13).

Lyme Disease

SNHL has also been reported in association with infection by another spirochete, Borrelia burgdorferi, the causative organism of Lyme disease. The organism is introduced into the skin by the bite of an infected tick of the genus Ixodes. The spirochete has particular tropism to skin, CNS, heart, joints, and the eyes. It is not fully clear which features are a result of disseminated infection and which result from the systemic inflammatory response. In the head and neck, Lyme disease is most commonly associated with facial paresis, particularly in children. There have also been reports of sudden SNHL or a Ménière-like syndrome.


Langerhans Histiocytosis

Langerhans histiocytosis (previously called histiocytosis X) describes a group of idiopathic disease caused by the abnormal proliferation of histiocytes. Histiocytes, normally benign cells found in the dermis or epidermis, accumulate in the skin, bone, lymph nodes, and visceral organs. This group is comprised of three diseases, eosinophilic granuloma, Hand-Schüller-Christian disease, and Letterer-Siwe disease, which describe progressively more aggressive and widespread manifestations of the same underlying pathology. Patients with eosinophilic granuloma develop solitary osteolytic lesions without systemic manifestations. The course of this disease is typically benign, and patients often undergo spontaneous regression of their lesions. For those who do not, local excision of the granuloma or intralesional steroids can be performed. Hand-Schüller-Christian disease typically affects patients less than 5 years old, who develop multifocal osteolytic lesions with rare
extraskeletal involvement. Up to 25% of patients present with the triad of osteolytic skull lesions, exophthalmos, and diabetes insipidus. Letter-Siwe is the most aggressive of this group, presenting most commonly in children less than 3 years old, who develop disseminated disease with diffuse involvement of multiple organs. Prognosis is poor with most patients succumbing to the disease in childhood (21). Lesional biopsy for each of these diseases demonstrates characteristic tennis racket-shaped Birbeck granule on histology, the result of cytoplasmic inclusions bodies. In addition, diagnosis can be made by demonstrating the presence of the CD1 antigen with immunohistochemistry (21).

The otologic manifestations of these diseases result from the development of a granuloma within the temporal bone. As the granuloma expands, it can cause conductive hearing loss, otorrhea, facial nerve paralysis, vertigo, and SNHL depending on which anatomic structures the granuloma violates (22,23). For patients with systemic disease and a temporal bone lesion, systemic steroids are the first line of therapy, with etoposide, vincristine, and vinblastine reserved for refractory patients. For patients with disease localized to the temporal bone, surgical debulking can be performed with topical and intralesional injection of steroids. Radiation therapy has also been successful in treating temporal bone lesions refractory to resection (24).


Sarcoidosis is a chronic multisystem disorder characterized by the presence of noncaseating granulomas. Classically, patients present with pulmonary symptoms characterized by persistent cough and hilar lymphadenopathy on chest x-ray. In addition, they can develop a granulomatous skin rash, iridocyclitis, keratoconjunctivitis, hepatosplenomegaly, myalgias, arthralgias, and neuropathies. Laboratory examination typically demonstrates hypercalcemia and an elevated angiotensin-converting enzyme level.

The otologic manifestations of sarcoidosis can result from uveoparotid fever or granulomatous disease within the middle ear or temporal bone. Uveoparotid fever, or Heerfordt syndrome, describes the constellation of parotitis, uveitis, fever, and facial nerve paralysis (25). Temporal bone or middle-ear granulomas can result in conductive or sensorineural hearing loss and vestibular dysfunction. Primary treatment of sarcoidosis is accomplished with corticosteroids. Refractory patients can benefit from methotrexate, cyclophosphamide, and number of other immunomodulatory agents (26).

Wegener Granulomatosis

Wegener granulomatosis is a systemic vasculitis of medium and small blood vessels resulting in a triad of necrotizing granulomas of the upper airway, necrotizing glomerulonephritis, and systemic necrotizing angiitis. Though Wegener granulomatosis is due to an autoimmune process, it is included in this section on granulomatous disease given that the otologic manifestations are mostly due to granulomatous involvement of the middle ear. Necrotizing granulomas can develop within the middle ear and mastoid, compromising the ossicular chain and eustachian tube function, resulting in a conductive hearing loss. This is more common than inner ear disease, but 8% to 20% of patients with Wegener granulomatosis do develop SNHL that is likely more similar in etiology to autoimmune disease as is discussed later in this chapter (27,28).


Autoimmune inflammation of the inner ear may be part of a systemic autoimmune syndrome or may occur in isolation as an organ-specific process. The most common autoimmune diseases that affect the ear are Cogan syndrome, polyarteritis nodosa (PAN), rheumatoid arthritis, relapsing polychondritis, and Wegener granulomatosis. The clinical presentation and pathophysiology of these diseases’ otologic manifestations are reviewed in this section. Several of these diseases have also been associated with cases of sudden hearing loss and histopathologic evidence of labyrinthitis (29). When autoimmune inflammation of the inner ear occurs as an organ-specific process, we refer to this as AIED, a relatively recently identified disease about which much remains unknown.

May 24, 2016 | Posted by in OTOLARYNGOLOGY | Comments Off on Otologic Manifestations of Systemic Disease: Includes Autoimmune Inner Ear Disease

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