Учебники / Auditory Trauma, Protection, and Repair Fay 2008

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He described 18 patients who had vestibular dysfunction as well as progressive bilateral hearing loss worsening over several weeks to months. In each case, an extensive workup for neoplastic and infectious etiologies was negative. Nearly all of the patients went on to demonstrate a dramatic response to immunosuppressive therapy, specifically dexamethasone concurrent with cyclophosphamide. This landmark publication began a new era where otolaryngologists became aware of AIED as one of the few treatable causes of sensorineural hearing loss.

2.2 Epidemiology

The true incidence of AIED is difficult to estimate. Confounding factors include similarity in presentation to Ménière’s syndrome, a much more common audiovestibular disorder, as well as a lack of confirmatory laboratory tests or radiological imaging diagnostic for AIED. Current estimates of AIED’s incidence place it behind idiopathic sudden sensorineural hearing loss (Rauch 1997), which has been estimated to involve 1 in 5,000 to 1 in 10,000 individuals per year (Ruckenstein 2004). AIED is therefore currently considered a rare disorder. Although AIED can affect patients at any age, it is more common in adults than in children. A recent review of 67 AIED patients found an age range from 18 to 70 years old with an equal male to female ratio (Harris et al. 2003).

AIED can be divided into two subtypes: patients with a known systemic autoimmune disease and patients without systemic autoimmune symptoms or diagnosis. The AIED patients without other systemic autoimmune disease constitute the majority of cases (70%), making the recognition of this illness difficult to separate from other progressive forms of hearing loss (genetic, viral, metabolic, toxic) that may have similar presentations (Hughes et al. 1988; Harris and Keithley 2002).

3. Immunology of the Inner Ear

Analogous to the central nervous system, the inner ear is separated from the systemic circulation by a blood–labyrinthine barrier that allows the inner ear to generate separate compartments containing high concentrations of both potassium in the endolymph and sodium in the perilymph, compartments that are critical for the normal functioning of the vestibular and auditory systems. Although the passage of immunoglobulins through the blood–labyrinthine barrier is restricted, immunoglobulins can be found within the inner ear at roughly 1/1000th the level present within the serum. IgG is the most abundant immunoglobulin found within the inner ear, with IgA and IgM also present (Palva and Raunio 1967, Mogi 1982).

Because of the existence of this blood–labyrinthine barrier, the inner ear has long been considered an immunologically privileged end organ incapable of participating in the immune response. However, research by Harris and coworkers has disproved this premise, and we now understand that the inner

ear can participate as the afferent limb of an immune response, capable of local antigen processing, release of proinflammatory cytokines, and recruitment of immunocompetent cells from the systemic circulation (Harris 1983; Harris and Ryan 1984; Tomiyama and Harris 1986; Fukuda et al. 1992). Further, it has been demonstrated that antibodies can be produced locally within the inner ear, and the secondary immune response to an antigen previously processed by the inner ear leads to a much higher systemic antibody level than is seen with the primary response. This secondary response is also independent of cerebrospinal fluid or serum, proving the inner ear’s participation in immune surveillance and processing (Harris 1989).

A critical component of the immune response is the release of proinflammatory cytokines when antigen arrives within the inner ear. These cytokines include tumor necrosis factor- (TNF- ), interleukin-1 (IL-1 ), and IL-6 (Satoh et al. 2003). The antigen must be processed and presented by immunocompetent cells just as in other parts of the body. Current research implicates the endolymphatic sac and the surrounding perisaccular tissues as the main antigen processing center of the inner ear. The endolymphatic sac is likely responsible for the generation of both the local response of the inner ear as well as the subsequent recruitment of the systemic immune response. Several facts substantiate this claim. The required cells for immunologic processing and presentation are present in the endolymphatic sac and perisaccular tissues. Specifically, lymphocytes including T-cells, macrophages, and B cells bearing IgM, IgG, and IgA have been identified within the endolymphatic sac but not within the cochlea (Takahashi and Harris 1988). Further, obliterating either the endolymphatic sac or the endolymphatic duct results in a much decreased immune response of the inner ear (Tomiyama and Harris 1986). In addition, horseradish peroxidase injected into the inner ear was found phagocytosed within hours of injection in a distribution consistent with uptake and processing by the endolymphatic sac and not the cochlea (Harris et al. 1997).

Once the antigen has been processed by these cells residing in and around the endolymphatic sac, proinflammatory cytokines are released, which results in the recruitment of a variety of cells and further elaboration of cytokines. The release of interleukin-2, platelet endothelial cell adhesion molecule 1, and other mediators from the endolymphatic sac are thought to cause an increased expression of intercellular adhesion molecule one (ICAM-1) as well as other surface molecules on the spiral modiolar vein (Suzuki et al. 1994; Takasu and Harris 1997). These steps are all critical for the diapedesis of specific systemic cells. Polymorphonuclear cells as well as macrophages enter the inner ear as early as 6 h after antigenic challenge. In the cochlea, the main conduit for entry has been identified as the spiral modiolar vein (Harris et al. 1990), with additional contributions from neighboring dilated bone marrow channels (Yamanobe et al. 1993).

Within the cochlea, immunoglobulin-bearing cells are also seen relatively early in the immune response (Ryan et al. 1997). IgG-bearing cells can be found as early as the first day after antigen challenge, with IgM-bearing cells found shortly

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thereafter. T-helper cells are noted in the endolymphatic sac approximately 24 h after antigenic challenge and gradually increase in their concentration with peak levels 2–3 weeks after antigen stimulation. T-suppressor cells can be detected in the cochlea and endolymphatic sac 3 weeks after antigenic challenge. IgA also appears roughly at 3 weeks post antigenic challenge. Antigen-specific antibodies within the inner ear are a relatively late event occurring at 4–6 weeks after a primary antigen challenge. When an animal has been systemically sensitized before receiving an inner ear challenge with the same antigen, the secondary immune response is faster and more vigorous, peaking at 2 weeks and 10-fold larger than the primary response described in the preceding text (Harris et al. 1997).

4. Clinical

4.1 Presentation

Autoimmune inner ear disease typically presents as a sensorineural hearing loss rapidly progressive over weeks to months. Fluctuations in hearing levels are common and asymmetry of the hearing loss between ears is typical. Although the initial presentation can be unilateral, both ears are ultimately affected in approximately 80% of cases. Vestibular symptoms including imbalance, vertigo, and ataxia have been found in 65% to 79% of cases (Hughes et al. 1988; Broughton 2004). Patients also commonly have aural fullness and tinnitus, both of which may fluctuate and are correlated with exacerbations in hearing loss and vestibular dysfunction.

Autoimmune inner ear disease can be divided into organ-specific disease (involves inner ear alone) or non-organ-specific disease (involves inner ear along with another systemic autoimmune illness). The majority of patients have autoimmune inner ear disease in the absence of other systemic autoimmune disease. However, approximately one third of patients have autoimmune inner ear disease along with other systemic autoimmune illness, such as those listed in Table 5.1.

4.2 Diagnosis

Autoimmune inner ear disease lacks any imaging modality or definitive laboratory test that allows for confirmation of the disorder. Currently, the diagnosis of AIED is most often made using a combination of clinical findings combined with a response to immunosuppressive therapy. A typical patient has bilateral fluctuating sensorineural hearing loss and a variable degree of vestibulopathy. A systemic autoimmune disorder is found in roughly 30% of patients and may aid in the diagnosis. A classification scheme is provided as Table 5.2 (Harris and Keithley 2002).

Table 5.1. Systemic diseases associated with immunemediated hearing loss.

Polyarteritis nodosum

Cogan’s syndrome

Wegener’s granulomatosis

Behçet’s disease

Relapsing polychondritis

Systemic lupus erythematosus

Sjögren’s syndrome

Rheumatoid arthritis

Inflammatory bowel disease (ulcerative colitis, Crohn’s disease)

Susac’s syndrome

Idiopathic thrombocytic purpura

Scleroderma

Polymyositis

Dermatomyositis

4.2.1 Audiology

An audiogram may demonstrate either unilateral or bilateral sensorineural hearing loss. This hearing loss will often worsen over the ensuing weeks if the patient is left untreated. A recent review evaluated audiograms in 116 adults with AIED ranging from 18 to 70 years old. They found the mean six-frequency pure tone average was 52.4 dB in the better hearing ear and 65.4 dB in the poorer hearing ear. Similarly, the mean word recognition score was 71.4% in the better hearing ear and 44.7% in the poorer hearing ear (Niparko 2005). Although there is no specific audiologic pattern of hearing loss that is seen in AIED, the usual audiogram demonstrates a flat loss across all frequencies. Tympanometry is normal as the patients do not have middle ear disease unless they are affected by a systemic autoimmune disorder.

Electronystagmonography may reveal decreased responses on caloric testing. Rotational chair testing may show an asymmetrical gain with unilateral loss of vestibular function or reduced gain with phase lag consistent with bilateral vestibular loss.

4.2.2 Laboratory Tests

Using a Western blot against bovine inner ear antigens, a patient’s serum can be screened for the presence of antibodies against a 68-kDa protein. These antibodies were first discovered using the guinea pig model for autoimmune inner ear disease (Harris 1987). Guinea pigs were injected with bovine cochlear tissue and 32% developed sensorineural hearing loss. Analysis of the serum from the guinea pigs that developed hearing loss revealed an antibody specific for an inner ear antigen with a molecular mass of 68 kDa. Subsequent analysis of human serum in patients with rapidly progressive bilateral sensorineural hearing loss demonstrated antibodies to the same 68-kDa antigen using Western blot

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analysis. A recent study of 72 patients found 89% of patients who had active AIED were also found to have antibodies to the 68-kDa antigen (Moscicki et al. 1994). None of the 25 patients with inactive AIED had antibodies to the 68-kDa antigen. Further, of those patients with antibodies to the 68-kDa antigen, 75% responded to corticosteroid treatment. In contrast, only 18% of patients who were negative for antibodies to the 68-kDa antigen responded to corticosteroid therapy. In a separate study, Western blot analysis against the 68-kDa antigen of 82 patients with AIED had a sensitivity of 42% and a specificity of 90% (Hirose et al. 1999). However, in recent years, there has been a move away from the anti-68-kDa antigen assay to an anti-heat shock protein 70 assay because of the reported cross reactivity between the two antigens (Shin et al. 1997). With this shift in an antigenic target, the specificity of the assay has declined and there is a need to return to inner ear antigen as the antigen source for AIED diagnostic testing. Currently, the Western blot assay for antibodies against the 68-kDa antigen remains the most specific test for AIED and serves to predict the likelihood of steroid responsive disease.

Tests for cellular immunity, such as the lymphocyte transformation test and the lymphocyte migration inhibition test, may assist in the diagnosis of AIED (Rocklin 1980; Oppenheim and Shecter 1980). Nonspecific antigen tests can be used to identify circulating immune complexes. These include cryoglobulins, C1q binding assay, and the hemolytic complement assay CH50.

It is also important to screen for systemic autoimmune disorders that are correlated with AIED. Tests frequently used are the Antinuclear antibody (ANA), Erythrocyte sedimentation rate (ESR), Cytoplasmic antineutrophilic antibody (c-ANCA), Urinalysis (UA), Florescent absorption test for treponemal antibodies (FTA-ABS), and Venereal Disease Research Laboratory test for syphilis (VDRL). The FTA-ABS or VDRL are important tests used to exclude syphilis, which can also present with bilateral fluctuating hearing loss with vestibular symptoms.

4.3 Classification

Table 5.2. Classification of AIED (Harris and Keithley 2002).

Type Conditions

1Organ (ear)-specific

2Rapidly progressive bilateral sensorineural hearing loss with systemic autoimmune

disease - other autoimmune condition is present (see table 1)

3Immune-mediated Meni´ ere’s` disease

4Rapidly progressive bilateral sensorineural hearing loss with associated inflammatory

disease (chronic otitis media, Lyme Disease, otosyphilis, serum sickness)

5Cogan’s Syndrome

4.4 Treatment

4.4.1 Acute Therapy

When faced with a sudden drop in hearing threshold, the most effective initial treatment is the use of high-dose systemic steroids. The choice of oral prednisone (60 mg/day) or Solu-Medrol (1–2 g IV per day) is up to the practitioner. We recommend oral prednisone for 3–4 weeks to initially manage the acute hearing loss. If the hearing improves, we begin a slow taper. If once again the hearing falls with the reduction of steroid dosage, the prednisone at high doses is restarted and plans are made to move to the chronic treatment strategies as discussed in the following subsection. If hearing does not improve after the first course of high dose prednisone for 1 month, no further immunosuppressives are given as this indicates a lack of steroid sensitivity. Plasmapharesis has been used successfully in treating patients with AIED, and some investigators advocate its use in patients who have not responded to corticosteroid therapy (Luetje and Berliner 1997).

4.4.2 Chronic Therapy

The attempt here is to manage patients with steroid-sparing medications so that the lowest dose of prednisone possible is used. In this scenario, the patient’s hearing has proven to be steroid dependent, and any reduction in dose results in abrupt hearing loss that often is preceded by fullness and loud tinnitus. Longterm corticosteroid therapy has substantial risks and side effects including peptic ulcers, mood disorders including suicidal ideation, insomnia, truncal obesity, moon facies, hyperglycemia, hypertension, immunosuppression, and avascular necrosis of the femoral head.

Consequently, the patient is routinely seen by our rheumatologists and together we find a steroid sparing medication to institute before we begin a steroid taper. A recent multi-institutional trial evaluated the efficacy of methotrexate (Trexall) in the treatment of AIED and found no benefit (Harris et al. 2003). Cyclophosphamide (Cytoxan) is a potent immunosuppressant, but the side effects are prohibitive. Bladder toxicity with the potential of bladder carcinoma, sterility, and bone marrow suppression with leukocytopenia are significant risks when using this medication. Typical dosing is 2–5 mg/kg per day each morning with heavy fluid intake to minimize the bladder toxicity. A peripheral blood smear must be performed periodically to monitor for the development of leukocytopenia. Tumor necrosis factor antagonists such as Remicade (infliximab), Enbrel (etanercept), and Humira (adalimumab) as well as the anti-B cell agent Rituxan (rituximab) are undergoing active investigation for use in AIED. There certainly will be many more biological modifying drugs developed in the years ahead that may be found to suppress the immunological damage that this illness causes in the inner ear without side effects that are unpleasant or life-threatening.

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4.4.3 Experimental Therapy

Here the notion is to apply sound logic to the treatment of AIED without specific data to support the regimens. It is always important to remember that these unproven methods need to be studied in a randomized clinical trial to prove their efficacy and safety. Currently, it is popular to recommend intratympanic steroids or even intratympanic biological modifying drugs to the middle ear with the hopes that they will cross the round window membrane and act directly on the inner ear. Of the steroid preparations, dexamethasone and methylprednisolone are the agents of choice. The dose and timing of these medications has not been established, nor has their efficacy been proven over and above systemic steroids; however, they do offer the theoretical benefit of not causing systemic side effects seen with the latter route. There is also the possibility that a TNFblocker could be instilled directly into the middle ear with the benefit of getting high dose local effects compared to the rather meager benefit recently reported using systemic Enbrel (Matteson 2005; van Wijk et al. 2006).

5. Animal Models for Autoimmune Inner Ear Disease

The first attempt to create an animal model for autoimmune inner ear disease was made by Bieckert in 1961. He immunized guinea pigs with isologous inner ear tissue and on sacrifice found lesions within the cochlea. However, he was not able to show any evidence of a cellular or humoral immune response to the inner ear tissues (Bieckert 1961). Shortly thereafter, Terayama immunized guinea pigs with isologous cochlear tissue in Freund’s adjuvant and also documented lesions within the cochlea. He too could not demonstrate any cellular or humoral immune response to inner ear tissues (Yoshihiko 1963).

Yoo et al. (1983) developed an animal model for immune-mediated hearing loss based on type II collagen. Rats were immunized with native bovine type II collagen and developed sensorineural hearing loss as well as vestibular dysfunction; they also developed antibodies to the native bovine type II collagen. Histopathologic evaluation revealed perivascular lesions within the cochlear artery including a mononuclear cell infiltration around the artery with thickening of the endothelial cells of the vessel. Immunofluorescence demonstrated IgG deposition within the vessel wall, the perivascular fibrous tissue, and the bone surrounding the cochlear and vestibular arteries. There was also a mild fibrosis in these vessels. Spiral ganglion cell degeneration was found along with swelling of the ganglion cell bodies and pyknotic nuclei displaced towards the axonal poles of the cells. The organ of Corti, stria vascularis, and cochlear nerve showed no evidence of injury at 1 month with only mild atrophic changes at two months. No pathologic changes could be found within the vestibular system. Interestingly, rats immunized with type I collagen or with denatured type II collagen did not develop sensorineural hearing loss or vestibular dysfunction.

Subsequent animal experiments have also demonstrated autoimmune inner ear damage (Harris 1983). Specifically, when a foreign protein antigen, in this

case keyhole limpet hemocyanin (KLH), was injected into the inner ear of naïve animals, a systemic immune response could be measured including elevation of inner ear and serum anti-KLH antibody levels. Importantly, no change in hearing levels occurred during this process. When the identical experiment was performed on animals that had been previously systemically exposed to KLH, a more vigorous systemic immune response was witnessed, with antibody levels within the perilymph elevated to levels far greater than in the naïve animals. More importantly, these animals developed hearing loss as determined by cochlear microphonic responses and also demonstrated histopathologic damage to the inner ear consisting of perilabyrinthine fibrosis, hemorrhage, loss of spiral ganglion cells, and degeneration of the organ of Corti. In these systemically exposed animals, inflammatory cells infiltrated the scala tympani and to a lesser extent the scala vestibule of the cochlea. The amount of damage was correlated with the degree of infiltration of the inflammatory cells within each turn of the cochlea. For example, the apical turns had fewer inflammatory cells and consequently displayed less damage and less hearing loss at the low frequencies. When the inflammation was severe, the cochlea went on to form a fibrous matrix followed by eventual calcification of the cochlea (Harris 1983).

Although these experiments demonstrated autoimmune inner ear damage via a specific antibody, the rise in the level of this specific antibody could have resulted from increased vascular permeability to serum immunoglobulins instead of local antibody production. To investigate this possibility, a study was designed that created a serum marker by systemically immunizing guinea pigs with bovine serum albumin (BSA). Guinea pigs once again had inner ear immunization with KLH, and an increase in anti-KLH perilymph antibody levels without a corresponding increase in anti-BSA levels was found. This proved that changes in vascular permeability was not the factor responsible for elevation in the increased perilymph antibody levels but in fact local production of the antibody within the inner ear was occurring (Harris 1984).

Harris went on to immunize guinea pigs with heterologous bovine inner ear antigen in Freund’s adjuvant. He found hearing deficits and lesions within their inner ears as well as circulating antibody titers to inner ear antigens both in the serum and in the perilymph. Interestingly, however, not all animals developed hearing loss. In fact, only 32% of the ears tested had significant deficits compared to control animals. In addition, of those animals that did develop hearing loss, the contralateral ear was affected only 50% of the time. There was also very little correlation between the magnitude of hearing loss and antibody levels within the serum or other markers of cellular immunity. Spiral ganglion cell degeneration, perivascular infiltration by plasma cells, nonspecific damage to the organ of Corti, and diffuse edema with hemorrhage could all be identified in these ears (Harris 1987).

More recently, a mouse monoclonal antibody was developed that binds to inner ear supporting cells in guinea pigs. When this monoclonal antibody, termed KHRI-3, was infused into the cochlea of guinea pigs, it induced hearing loss in the 25to 55-dB range in the majority of tested animals. Control animals had