Chapter 68. Sensorineural Hearing Loss (Immune-Mediated Inner Ear Disease)

• When sensorineural hearing loss occurs in the context of an inflammatory condition, it is referred to most appropriately as immune-mediated inner ear disease (IMIED).
• May be associated with disturbances of balance as well as hearing loss because the inner ear mediates vestibular function as well as hearing.
• May occur as a primary inner ear problem or as a complication of a recognized inflammatory condition such as Cogan syndrome, granulomatosis with polyangiitis (formerly Wegener granulomatosis), giant cell arteritis, Sjögren syndrome, and others.
• Symptoms include tinnitus, vertigo, nausea, and difficulties with two issues related to hearing: acuity and speech discrimination.

Sensorineural hearing loss (SNHL) is an idiopathic inflammatory disorder, either secondary to a known autoimmune disease or occurring as a primary form of disease limited to the ear. The anatomy of the inner ear is shown in Figure 68–1. SNHL is a common feature of some primary forms of vasculitis (eg, Cogan syndrome, granulomatosis with polyangiitis (formerly Wegener granulomatosis), giant cell arteritis). SNHL also occasionally occurs in association with systemic autoimmune disorders, such as systemic lupus erythematosus (SLE) and Sjögren syndrome. Finally, SNHL may represent an organ-specific inflammatory process confined to the inner ear. Injury to the stria vascularis associated with antibody deposition around vessels and vascular occlusion observed in temporal bone specimens is likely to impair the metabolic processes that support hearing transduction. Because hearing loss is often not the sole feature of this syndrome—vertigo, tinnitus, and a sense of aural fullness often occur as well—and because the symptoms respond frequently to immunosuppression, immune-mediated inner ear disease (IMIED) is the preferred term for this disorder when symptoms and signs are confined entirely to the ear. Devastating disabilities including profound deafness and severe vestibular dysfunction are potential sequelae of IMIED. Yet, if diagnosed promptly, IMIED is amenable to treatment. Unfortunately, the prognosis is difficult to gauge except in the setting of profound, sustained SNHL, in which case significant recovery of hearing is unlikely.

Several characteristics distinguish IMIED from other syndromes of inner ear dysfunction. First, its time course is relatively rapid. IMIED is analogous to rapidly progressive glomerulonephritis in that inner ear inflammation progresses to severe, irreversible damage within 3 months of onset (and often much more quickly). With IMIED, in fact, the complete loss of hearing within a week or two of symptom onset is not unusual. Second, IMIED is usually bilateral to some degree, albeit the left and right sides may be affected asymmetrically and asynchronously. Typically, weeks or months separate involvement of the two sides, but the interval may be as long as a year or more. Finally, although some cases of IMIED are marked by precipitous, irretrievable losses of inner ear function, others demonstrate fluctuating symptom patterns over a period of several months. Recurrent bouts of SNHL often lead to consistent decrements in hearing capabilities, causing profound hearing deficits in many patients over time.

Although IMIED usually occurs in middle-aged individuals, the syndrome has been described in young children and also in the elderly. Two thirds of the patients with IMIED are women.

Symptoms and Signs

Hearing

Hearing loss in IMIED may take two forms. First, patients may complain primarily of diminished hearing acuity (the ability to perceive sound). Crude assessments of hearing sensitivity using the mechanical sounds of a watch, the dial-tone of a telephone, or the rubbing of fingers, are inadequate to detect subtle but clinically significant deficits in hearing acuity. Second, patients may also note decreased discrimination (the ability to distinguish individual words). Communication problems arising from poor word discrimination often constitute the chief complaint. Patients with significant deficits in word discrimination are able to hear the sound of a voice on the telephone, but fail to understand what is being said. They also have difficulty participating in conversations conducted amid background noise. Understanding conversations in crowded rooms or restaurants is particularly problematic.

Otoscopy is usually normal in IMIED, even among patients with profound SNHL. In patients with SNHL secondary to granulomatosis with polyangiitis, otoscopy may reveal findings consistent with otitis media caused by granulomatous inflammation within the middle ear cavity, tympanic membrane clouding, or even rupture.

In granulomatosis with polyangiitis, conductive hearing loss caused by middle ear disease is more common than SNHL, but SNHL occurs with a frequency that is probably underrecognized because of failure to obtain audiologic testing in all patients. Conductive hearing loss in granulomatosis with polyangiitis results from a variety of mechanisms, including opacification of the middle ear cleft with fluid or discontinuity of the ossicular ear chain. In contrast, the ischemic sequelae of vasculitis are believed responsible for SNHL. Both vasculitis of the vasa nervorum and compression of the VIIth cranial nerve by granulomatous inflammation as it courses through the middle ear can cause peripheral facial nerve paralysis.

Two simple physical examination tests are useful in distinguishing SNHL from conductive hearing loss: the Weber test and the Rinne test. In the Weber test, a vibrating 512 Hz tuning fork is placed on an upper incisor tooth or mid-forehead. The tone will sound louder in the ipsilateral ear if conductive hearing loss is present, and in the contralateral ear if SNHL is present. The test can be repeated for higher frequencies. In the Rinne test, a vibrating 512 Hz tuning fork is first placed 3 cm from the opening of the ear and then in contact with the mastoid bone. A comparison is made between the loudness of the tone generated in air and that on the bone. A conductive hearing loss of at least 30 dB is suggested when bone conduction exceeds air conduction in loudness. A normal Rinne test (air conduction >bone conduction) in an ear to which the Weber has lateralized, suggests SNHL in that ear.

Balance

Otolaryngologists and neurologists, who should become involved in patients’ care if SNHL is suspected, should be expert at evaluating patients’ vestibulo-ocular reflexes (VORs). Other tests, including audiometric testing and electronystagmography, are also essential components of the work-up.

Evaluations of the VORs consist of assessments for nystagmus in response to repetitive head shaking, and for gaze stability during rapid lateral rotation of the head. By detecting head movement, the inner ear provides afferent input to the VOR upon which the central nervous system depends for accuracy in the compensatory saccadic movements of the eyes. Disturbance of the inner ear’s role in maintaining a stable image on the retina leads to a perception of dizziness, which is worsened by head movement and relieved at rest. The rapid changes in afferent input to the central nervous system associated with IMIED lead to VOR decompensation, an inability to maintain a stable retinal image, and a persistent illusion of movement known as vertigo.

The acute phase of vertigo resolves to motion-induced dizziness through central compensation after days to weeks. In the acute phase of vestibular decompensation, spontaneous nystagmus may be seen when visual fixation is suppressed (eg, in the dark or behind Frensel lenses). The VOR can be assessed for each ear separately at the bedside by asking the patient to fix her eyes on the examiner’s nose while the examiner quickly turns the patient’s head 30 degrees toward the ear in question. Normal VORs generate smooth, accurate compensatory ocular saccades. In contrast, abnormal VORs are associated with under- or overshooting of the eye movements, followed by a corrective saccade.

A feeling of perpetual motion known as oscillopsia is a disabling consequence of bilateral VOR loss. The presence of oscillopsia and bilateral vestibular hypofunction can be detected by comparing visual acuity with the Snellen chart while the head is at rest versus during head shaking. A difference in visual acuity of 3 or more lines is an indication of peripheral vestibular dysfunction. Larger decrements are expected in bilateral disease.

Electronystagmography provides objective measure and comparison between ears of peripheral vestibular function, more specifically the lateral semicircular canal. The vestibular electromyographic potential measured in the sternocleidomastoid muscle in response to stimulation of the saccule by low frequency sound assesses another component of peripheral vestibular function.

Eyes

Cogan syndrome, described in detail in Chapter 42, can be associated with virtually any form of ocular inflammation, including orbital pseudotumor, scleritis, and uveitis. The most characteristic ocular manifestation of Cogan syndrome, however, is interstitial keratitis. Granulomatosis with polyangiitis (see Chapter 32) also has a host of potential ocular complications. Diplopia, amaurosis fugax, and anterior ischemic optic neuropathy are common manifestations of giant cell arteritis. Aside from secondary sicca symptoms, the most common eye problem in SLE (see Chapters 21 and 22) is retinopathy, which may be associated with either retinal vasculitis or a clotting diathesis, such as that associated with antiphospholipid antibodies. Keratoconjunctivitis sicca is a hallmark of Sjögren syndrome (see Chapter 26).

Laboratory Findings

The results of routine laboratory test in IMIED are usually unremarkable. There is typically no indication, for example, of a systemic inflammatory response; acute phase reactants are usually normal. The measurement of several types of autoantibodies is highly appropriate, however, in the search for an underlying cause of SNHL that might have alternative treatment indications. Autoantibodies relevant to the assessment of a patient with SNHL are shown in Table 68–1.

Imaging Studies

Magnetic resonance imaging studies are essential to exclude tumors of the cerebellopontine angle.

Special Tests

Audiogram and Electronystagmogram

Formal hearing tests should be performed on any patient with a complaint of hearing loss. The audiogram (Figure 68–2A) is a graphic representation of the lowest volume at which individual tones ranging from 250 Hz to 8000 Hz can be distinguished. An audiogram from a patient with classic SNHL is depicted in Figure 68–2B. The reception threshold measures the lowest volume at which speech is heard. The discrimination score measures the ability to discriminate words. Electronystagmography measures ocular movement in response to various stimuli, including warm and cold caloric stimulation of the ears. This test assesses the functional strength and symmetry of the VORs in response to input from both ears. Audiometry and electronystagmography testing may confirm clinical impressions of inner ear dysfunction and quantify the degree of organ involvement.

Serologic Testing for Antibodies to the 68 kD Antigen

The impact of early diagnosis and treatment on long-term hearing prognosis in patients with IMIED has prompted the search for specific markers of inner ear inflammation. The sera of patients with rapidly progressive bilateral SNHL contain antibodies that react with a variety of antigens from human and bovine inner ears. However, antibodies to cochlear-specific antigens have low specificities for rapidly progressive SNHL. In contrast, antibodies to a non-organ specific protein, a 68-kD antigen found in the inner ear, kidney, brain, and other organs of non-human species (eg, cows), appear to have relatively high specificity for IMIED in humans. In a group of 72 patients with rapidly progressive bilateral SNHL, investigators found that 58% of participants possessed antibodies to the 68-kD antigen, compared to only 2% of normal participants and none of the participants with otosclerosis or Cogan syndrome (P <.01). This test may therefore be useful in helping establish the diagnosis of IMIED if the clinical scenario is compatible, but the test characteristics (sensitivity, specificity, positive, and negative predictive values) remain to be established firmly in the context of day-to-day practice.

Because the treatments for various inner ear disorders vary dramatically according to cause, precise distinction between etiologies is critical. Table 68–2 depicts the major disease categories that require exclusion in the work-up of patients with possible IMIED. The etiologies of inner ear dysfunction may differ in several respects: (1) their rates of progression; (2) their degrees of symmetry; and (3) and their relative effects on hearing and balance. The etiologies may be divided into six major categories: aging, trauma, tumors, infections, ototoxic drugs, and finally, cases presumed to be immunologic in nature.

Slowly progressive, symmetric loss of high frequency hearing without vestibular symptoms distinguishes hearing loss due to aging and chronic noise exposure from IMIED. In addition, rapidly progressive hearing loss and dysequilibrium due to ototoxic drugs, sudden acoustic trauma, or barotrauma can be excluded by taking a careful history. Meniere syndrome, a symptom complex of gradual, fluctuating hearing loss punctuated by episodes of vertigo, tinnitus, and aural fullness, is a common sequela to many causes of inner ear inflammation, including IMIED. In the absence of identifiable causes, the syndrome is termed Meniere disease.

Time course is the principal criterion for distinguishing Meniere disease from IMIED. In Meniere disease, hearing loss occurs over a period of several years, rather than the weeks or months characteristic of IMIED. Meniere disease is also usually limited to one ear, but delayed involvement of the contralateral ear occurs in approximately one third of cases. Because IMIED is more likely to respond to the early institution of aggressive immunosuppression, distinguishing between these two disorders is critical.

Other causes of rapid changes in auditory and balance function are difficult to distinguish from IMIED by history alone. For example, tumors that compress the eighth cranial nerve (eg, schwannomas at the cerebellopontine angle) cause asymmetric hearing loss with variable rates of progression, ranging from days to years. MRI with gadolinium is essential to exclude such tumors. Rapid increases in intracranial or middle ear pressures (eg, as induced by trauma or a forceful Valsalva maneuver) may lead to a breach in the bony capsule of the inner ear. This condition, known as a perilymph fistula, produces rapid unilateral hearing loss accompanied by vertigo. Patients with perilymph fistulas are candidates for prompt surgical repair.

Bacterial and viral causes of inner ear dysfunction, including meningitis, may lead to swift, dramatic, irreversible hearing loss. These must be excluded quickly with appropriate cultures and serologies. Table 68–2 includes a partial list of infections associated with inner ear disease. Syphilis deserves special emphasis because of the many similarities between otosyphilis and IMIED. Syphilitic complications span the entire spectrum of inner ear disease, ranging from the sudden onset of hearing loss and vertigo associated with secondary syphilis to the gradual hearing loss associated with latent and tertiary stages of disease (sometimes accompanied by Meniere syndrome). Specific treponemal tests, eg, the fluorescent treponemal antibody absorption (FTA-ABS) assay, are indicated in all patients with unexplained hearing loss. Non-treponemal tests such as the rapid plasma reagin (RPR) have unacceptably high false-negative rates in latent and tertiary infection. Susac syndrome is a poorly understood disease entity, marked by encephalopathy, branch retinal artery occlusion, and SNHL.

In the absence of significant numbers of rigorous, controlled studies, the treatment approach for IMIED is based largely on anecdotal experience, case series, and inference from the treatment of related conditions. Because of the devastating nature of severely impaired hearing and vestibular function, IMIED should be regarded in the same fashion as any other threat to vital organ mediated by an immunologic injury. In such conditions, aggressive immunosuppression—glucocorticoids and, in most cases, a cytotoxic agent—may halt the inflammatory response and prevent permanent organ damage. In contrast, failure to treat these disorders promptly leads to substantial, irreversible organ dysfunction within a brief time.

Numerous case reports and small case series demonstrate the responsiveness of IMIED to immunosuppression in its early stages, including recovery of vestibular function. In steroid-responsive cases, intratympanic glucocorticoids offer an alternative to systemic therapy with the potential of maintaining function with serial treatments. The authors’ approach to the treatment of IMIED is guided by the concept that if IMIED is worth treating (ie, if significant inner ear function appears recoverable), it is worth treating aggressively. Thus, in the setting of rapidly progressive SNHL, treatment with 1 mg/kg/d of prednisone, not to exceed 80 mg/day, is instituted. If there is significant improvement in auditory and vestibular function within 2 weeks, prednisone is continued at this dosage for a total of 1 month, and then tapered to discontinuation over an 2 additional months. In patients with recurrent disease, some maintenance prednisone (eg, 5–10 mg/d) may be prudent. Intratympanic glucocorticoid therapy is administered serially to maintain initial benefit in response to a glucocorticoid pulse in patients who cannot tolerate prolonged therapy because of side effects or are losing benefit during or following the taper. A variety of concentrations have been suggested although the authors currently use buffered dexamethasone (12 mg/mL) which is injected into the middle ear where it remains for 30 minutes with the patient supine, and is then suctioned.

If hearing and balance deteriorate despite prednisone or do not improve significantly within the 2 weeks of treatment, cyclophosphamide (2 mg/kg/d) can be added to the regimen. Cyclophosphamide can also be considered if patients do not maintain audiovestibular gains during their prednisone tapers. Because of the potential toxicities of cyclophosphamide, treatment beyond 4–6 months is not advised. Rather, if a convincing treatment response has been established, switching to another immunosuppressive agent (eg, methotrexate, up to 25 mg/week; azathioprine, 2 mg/kg/d; or mycophenolate mofetil, up to 1500 mg twice daily) is recommended after this time. At present, there are no data regarding the use of biologic agents to make firm recommendations on treatment with these medications.

Unless active disease in other organ systems justifies continuation of significant immunosuppression, the maintenance of such therapy after irreversible organ damage (ie, profound hearing loss) has occurred places patients at risk for treatment complications with little potential benefit. In the setting of profound hearing disturbances despite aggressive immunosuppression, the hearing that a patient may derive from a cochlear implant (Figure 68–3) may render this the most appropriate course of action. Consequently, if patients have not demonstrated a response by the end of 3 months of therapy, the medications should be discontinued.

The treatment of SNHL associated with granulomatosis with polyangiitis, Cogan syndrome, and other primary disorders are discussed in their appropriate chapters.

Seropositivity for antibodies to the 68-kD antigen may correlate with both active disease and the likelihood of a treatment response. One study found that antibodies against the 68-kD antigen were significantly more common in patients with rapidly progressive SNHL of less than 3 months duration compared with patients whose hearing loss had been present for more than 3 months. Compared to patients who did not have antibodies to the 68-KD antigen, seropositive patients were also more likely to respond to glucocorticoid therapy. These observations support an association between antibodies to the 68-kD antigen and the early stages of IMIED. Other studies of antibodies directed against this antigen, however, have been significantly less conclusive about its relevance to IMIED.

All patients with functionally significant bilateral hearing loss should be supplied with appropriate hearing aids. When speech discrimination remains poor in both ears despite maximal medical therapy and the use of powerful hearing aids, the patient may be a candidate for cochlear implantation. Cochlear implants process and deliver sound to the auditory nerve in the form of encoded electrical signals, increasing both hearing acuity and speech understanding.

For patients with dizziness due to a significant loss of peripheral vestibular function, compensation by the central nervous system is effectively enhanced through a program of vestibular rehabilitation. Such programs, administered by appropriately trained physical therapists, promote a variety of strategies to maintain balance and minimize fall risk. In the treatment of dizziness, long-term use of vestibular suppressant drugs (eg, meclizine) should be avoided because they impede the development of central compensation mechanisms.