Elias Toubi and Aharon Kessel
Introduction
Evidence now exists that inner-ear pathology is frequently associated with immune dysfunction, including the presence of anticardiolipin antibodies (aCL) in the sera of these patients.
The pathogenesis of sensorineural hearing loss (SNHL) is still considered idio- pathic, in most cases. Sudden deafness, severe hearing loss of acute onset, is usually unilateral but may also occur bilaterally as well. Patients with progressive SNHL, develop bilateral progressive hearing loss over the course of a few days to 1–2 months, although as many as 20% initially present a unilateral loss. Both disabilities occur in previously healthy subjects, with an equal preponderance among males and females.
In addition to auditory symptoms, these patients may also present vestibular complaints, such as true vertigo, lightheadedness, or ataxia. Tinnitus and aural pressure are also frequent symptoms, and may occur in one half and one third of all patients, respectively.
The potential role of autoimmunity in the pathogenesis of hearing loss was first reported by McCabe in 1979 [1], who described a pattern of bilateral SNHL charac- terized by rapid progression over days to months. This was based on the finding of a positive lymphocyte migration inhibition assay to cochlear antigens and the steroid responsiveness of the hearing loss in such patients. Additional support includes the following: both cellular and humoral elements of the immune system can normally be identified in inner-ear tissue; animal models demonstrate inner-ear damage after immunization with inner-ear tissue extracts; and such an injury is transferable with sensitized T cells; human SNHL can occur in the context of systemic immunological disease; and SNHL can be treated by immunosuppressive therapy [2–5]. However, the definite proof of an autoimmune etiology is still lacking because in most studies the exact nature of the immunizing antigenic epitope(s) has not yet been identified.
The Association of SNHL with Autoimmune Disease
During the last decade many reports described the association of SNHL with various autoimmune disorders such as: systemic lupus erythematosus (SLE), Sjögren syndrome, chronic ulcerative colitis, rheumatoid arthritis, polyarthritis
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nodosa, polymyositis, Hashimoto’s thyroiditis, and Cogan’s syndrome [6–9]. The beneficial effect of immunosuppressive therapy observed in some of these patients supports the immune-mediated etiology. It was stressed that immediate treatment with corticosteroids or other immunosuppressive agents is essential because delay may lead to irreversible hearing loss [10]. The benefit of plasmapheresis in patients with suspected immune-mediated hearing loss was evaluated: improved hearing was observed in 8/16 (50%) patients and only 25% of the patients required addi- tional immunosuppressive maintenance therapy [11]. In 1986, Bowman et al [12], prospectively tested the hearing status of 30 patients hospitalized during SLE flares and observed an 8% incidence of substantial, previously undetected hearing loss. In the same year, Caldarelli et al [13] reported profound SNHL of the right ear in a 51-year-old woman, followed 3 weeks later by a similar finding in her left ear. This was concomitant with symptoms of her newly diagnosed SLE. In 1992, Kobayashi et al [14], described bilateral SNHL in a 32-year-old woman that improved dramati- cally after plasmapheresis, 2 years before the diagnosis of SLE was established. They suggested that circulating immune complexes or antiphospholipid antibodies (aPL) might play a pathological role in the hearing impairment in SLE patients. In 1995, Kataoka et al [15] documented another case of intermittent bilateral SNHL in con- junction with SLE.
In the same year, Andonopoulos et al [16] reported an association between SNHL and SLE, without correlation to SLE disease activity, concluding that factors other than inflammation may be involved in the pathogenesis of this disorder. Later, Sperling et al found that out of 84 SLE patients, 31% were reported to suffer from aural symptoms, such as tinnitus and hearing loss, suggesting that these findings are also related to the immune complex nature of the disease [17].
In yet another study, the symptoms of SNHL were observed in 38% of 37 unse- lected systemic sclerosis (SSc) patients, suggesting that SSc may be included among the autoimmune diseases which may cause audiovestibular disturbances [18]. The association between Behcet’s disease and SNHL was also reported in 1 patient who had fluctuating hearing loss, tinnitus, and dizziness, proposing a causative relation- ship between autoimmune vasculitis and endolymphatic hydrops [19].
Animal Models for Immune-mediated SNHL
To aid in the investigation of SNHL, several animal models were introduced. In 1983, Yoo et al [20] immunized rats with native bovine type II collagen, a major structural element of the inner ear, and induced SNHL in these animals.
Ruckenstein et al [21] proposed the MRL-lpr/lpr mouse strain as a potential model
of autoimmune inner-ear pathology (a strain known to develop an SLE-like disease
at the age of 4–5 months) in which the authors observed cochlear pathology in 6/11
animals of this age. Based on the above, Iwai et al [22] demonstrated in severe com-
bined immunodeficient (SCID) mice, infused with MRL-lpr/lpr spleen cells, the
induction of cochlear damage which normally would not have developed in such
animals. In a recent study, Billings [23] described a mouse model of CD4+ T
cell–mediated autoimmune SNHL induced by immunization with peptides from the
inner ear–specific proteins cochlin and β-tectorin. However, it is not yet clear how
accurately this model reflects events occurring in the spontaneous idiopathic
disease.
Immunological Profile in Sensorineural Hearing Disorders
Laboratory studies of peripheral blood lymphocytes from patients suffering from SNHL and serological assays of antigen-specific immune responses to sonicated inner-ear antigen preparations have provided evidence that the disease may have an autoimmune etiology. The two tests most commonly used are the lymphocyte trans- formation test and the Western blot immune assay [24].
In 1993, Mayot et al [25] reported in 57 individuals with SD (n = 17; group 1) and progressive SNHL (n = 40; group 2) an abnormality of the T-cell subgroups in peripheral blood. The reduced presence of CD3+ and CD4+ cells was observed in group 1, and there was marked decrease of CD8+ cells for both groups. In addition, antinuclear and antithyroid antibodies were frequently detected in the sera of group 2 patients (75%), whereas anticochlear and anticartilage antibodies were present in both groups with a similar frequency (71%). Boulassel et al [26] used two-dimen- sional gel electrophoresis and immunoblot analysis to define, at the molecular level, the inner-ear auto-antigens recognized by auto-antibodies in the sera of patients suffering from inner-ear diseases. Forty-four percent of the patients’ sera had anti- bodies for several inner-ear proteins, of which the 30, 42, and 68 kDa proteins were found to be the most reactive. The 30 and 42 kDa inner-ear proteins were found to be the major peripheral myelin protein P0 and the beta-actin protein, respectively.
A study by Shin et al [27] using a Western blot immune assay suggested that approximately 40% of patients with rapidly progressive SNHL have antibodies to 68 kDa (heat-shock protein-70; hsp-70) inner-ear antigen. Such immunoblot testing provides 58% sensitivity and 98% specificity for hsp-70 antibodies.
In a different study, sera from patients with various inner-ear diseases, especially Meniere’s disease, were investigated by a Western blot against guinea pig inner-ear proteins. Out of 45 patients, 24 (53%) with various inner-ear diseases had antibod- ies against inner-ear proteins compared with 0/10 in control subjects without inner- ear diseases. Of the 10 proteins that showed a positive reaction with the patient’s sera, the 28-kDa band was unique in that it appeared only in the membranous frac- tion of the inner-ear proteins and was highly positive (28%) in reaction with Meniere’s disease patient’s sera. These results suggest that the antibody to the 28-kDa protein may be a candidate for detecting autoimmune inner-ear disease [28].
In another study, 16/18 SLE patients had antibodies to guinea pig inner-ear anti- gens (detected by immunobloting), whereas none were detected in the sera of the 11 normal subjects. This suggested that the inner ear might be one of the targets involved in SLE [29]. In this regard immunological abnormalities were demonstrated in 25/50 patients with SNHL; high immunoglobulin titers were observed in 18/50. Six patients were seropositive for antinuclear antibody and rheumatoid factor, whereas 2/50 revealed high anti-DNA titers [30]. In addition, abnormal low serum complement levels were detected in 6 cases. In summary, based on all of the above facts, sen- sorineural hearing loss is associated with immunological dysregulation.
Sensorineural Hearing Loss and APS
Because the internal auditory artery is an end artery, disturbed circulation of the
inner ear has long been suggested as the cause of sudden SNHL. In 1994, de Kleyn
postulated a central vascular lesion in many SNHL cases [31]. Later, some authors have attributed these symptoms to a deficient homeostasis, often in conjunction with additional risk factors for vascular disease, such as arteriosclerosis and high blood viscosity. Others have postulated a viral cause, having a detrimental effect on the rheologic properties of blood.
Primary APS and SNHL
Because microthrombosis associated with aPL is known to affect either dermal or retinal vasculature, a similar involvement of the cochlear vessels could be envi- sioned, causing sudden SNHL.
In 1996, Hisashi et al [32] reported 3 female patients with sudden SNHL having elevated levels of aCL in their sera: 1/3 had IgM aCL and 2/3 had IgG aCL.
Corticosteroid therapy was effective only in the first patient, whereas in another case, hearing loss improved only after adding prostaglandin E and ticlopidine to the corticosteroids. The author concluded that corticosteroids as well as prostaglandin E and ticlopidine therapy might be effective in patients with SNHL with aCL.
In 1997 we reported our results on the presence of aCL in the sera of patients with SNHL [33]. Low-to-moderate positive aCL to one or both IgG/IgM isotypes (range, 18–35 units) were found in 8/30 (27%) patients, whereas none were detected in healthy controls (P < 0.02). Another study supported the notion that primary APS is associated with the development of SNHL. In the sera of 55 patients with SD and 80 with progressive SNHL, aCL was present in 49% and 50% of these patients, respectively [34]. The conclusions from these studies were missing as the require- ment for a true positive aCL test is based on at least two consecutive seropositive aCL results that were not performed in these studies. It is also important to note that anti– β
2-glycoprotein I (anti– β
2-GPI) antibodies were not analyzed in these patients. Recently, in an extended study we assessed 51 patients (31 women and 20 men) who met the diagnostic criteria of SNHL. We found low to moderately posi- tive titers of aCL in 16 patients (31%) compared with 2 (6%) in the healthy controls (P = 0.004). Six patients (12%, all aCL positive) were also positive for anti– β
2-GPI.
Three months later positive aCL persisted in 7 (14%) patients, four of whom were also positive for anti– β
2-GPI [35]. This is consistent with the knowledge that anti–β
2-GPI antibodies are more specifically associated with thromboembolism [36].
Tests for antibodies to CMV, EBV, and HCV were found negative in all aCL-
positive patients. This “positiveness” for aCL together with anti– β
2-GPI further sup-
ports the assumption of an association between SNHL and aPL in some patients,
whereas in others it is of a transient character. Although a transient increase in aCL
is not considered pathogenic, it is possible that in some cases the increase in anti-
body titer is capable of inducing transient vascular damage and, hence,
microthrombosis. The pathogenic effect of aCL/anti–β
2-GPI induced by viral or
bacterial peptides is the subject of many recent investigations. It is generally
believed that aCL induced by infection (such as EBV or CMV) are independent of
β
2-GPI , and do not appear to be pathogenic. Some reports suggest, however, that
certain infections may induce β
2-GPI–dependent aCL as well as clinical features of
APS. This finding strongly suggests that viral antigens can induce aCL and some- times anti– β
2-GPI positivity in humans, and that these antibodies cross-react with the self-phospholipids and consequently are potentially pathogenic [37, 38].
Secondary APS and Progressive SNHL
In the past SNHL has been reported to be one of the symptoms complicating autoimmune diseases, but only recently its association with aCL seropositive data was reported. In 1993, Hisashi et al [39] reported on the occurrence of SNHL in a patient with SLE who was also seropositive for IgG aCL. In 1995, Casoli and Tumiati [40] reported, in a 55-year-old woman with Sjögren syndrome and aCL, seropositiv- ity of IgG and IgM isotypes. She developed a sudden SNHL in association with vertigo, suggesting the presence of atypical Cogan’s syndrome.
In a different study [41], 30 women suffering from Sjögren syndrome were evalu- ated for audiovestibular disorders, in comparison with 40 healthy age-matched female controls. In 14/30 patients (46%), SNHL was found, compared to only one control subject (2.5%). Nine of the above 14 patients (64%) tested seropositive for aCL compared with 3/40 controls. This study suggested that SNHL in Sjögren syn- drome is correlated with the presence of aCL .
Naaredrop and Spiera [42] also reported 6 patients who developed sudden deafness in association with moderate-to-high levels of aCL and/or a positive lupus anticoagulant test.
Many studies evaluated the association between autoimmune SNHL and various viral infections, such as parvovirus B19, measles, mumps, and influenza, suggesting that these viruses may be of possible etiology in this inner-ear disease [43, 44]. On the other hand, the finding of positive aCL is also frequently related to such viruses, but without clear evidence that aCL may be the cause of recurrent thrombosis.
However, some studies reported on the association between thrombosis and infec- tious induced aPL [45].
Therefore, it is important to analyze the possible relationship between SNHL, aCL, and various viral infections. If such a positive association can be established, the use of anticoagulant therapy should be its logical consequence [46].
Closing Comments
The etiology of SNHL remains idiopathic in most cases, despite many attempts to
relate this condition to infectious diseases, immune-mediated vascular disorders,
or microthrombosis [47]. In some reports, SNHL was shown to be associated with
the presence of various auto-antibodies and/or the dysregulation of cellular immu-
nity. Reports by the authors and by others describe an association between SNHL
and aCL [35], raising the speculation that this disorder is microthrombotic in
origin. The persistence of aCL over time and the coexistence of anti–β
2-GPI in some
patients further support this assumption. In the absence of histological or imaging
tool to demonstrate microthrombosis in the inner ear of patients with SNHL and
APS, the next rational step is the assessment of the use of anticoagulant therapy in
such patients.
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