Hearing loss in autoimmune disorders: Prevalence ...

AUTREV-02157; No of Pages 9 Autoimmunity Reviews xxx (2018) xxx–xxx

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Review

Hearing loss in autoimmune disorders: Prevalence and therapeutic options☆ Patrizia Mancini a, Francesca Atturo a,⁎, Alessia Di Mario a, Ginevra Portanova a, Massimo Ralli b, Armando De Virgilio c, Marco de Vincentiis b, Antonio Greco a a b c

Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00100 Rome, Italy Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00100 Rome, Italy Otorhinolaryngology Unit, Humanitas Clinical and Research Center, Viale Manzoni 56, 20089, Rozzano (MI)

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Article history: Received 28 December 2017 Accepted 2 January 2018 Available online xxxx Keywords: Autoimmune inner ear disease Immune-mediated inner ear disease Cochlear implant Hearing loss

a b s t r a c t The objective of this study was to review our current knowledge relative to the correlation between sensorineural hearing loss (SNHL) and autoimmune diseases, focusing on the prevalence of hearing loss in different pathologies and possible therapeutic approaches. A review of the literature on hearing loss in different forms of autoimmune disease has been carried out, with emphasis on incidence and prevalence of SNHL. Therapeutic protocols have been assessed including both conservative medical and rehabilitative methods. Cochlear implant outcomes have been investigated. The prevalence of hearing loss in autoimmune and immune-mediated inner ear diseases, as referred by case reports or single-center statistics, is widely variable. More difficult is the evaluation of severe/profound SNHL, usually reported in relation to cochlear implantation. Though these patients represent ideal candidates for cochlear implantation, as they become deaf after years of hearing; the associated systemic disease, the specific damage on inner ear structures and the medication taken may influence the result of cochlear implantation. The main problem is the cochlear fibrosis or ossification that has been found to affect 50% of implanted ears in patients suffering from autoimmune and immune-mediated SNHL. Hence, in the presence of severe/profound SNHL earlier implantation may be indicated before post-inflammatory obliterative changes to the cochlea. © 2018 Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Incidence and prevalence of systemic autoimmune inner ear disease. 3. Therapeutic approaches to hearing loss . . . . . . . . . . . . . . 4. Cochlear implant outcomes in autoimmune disorders . . . . . . . 5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Autoimmune sensorineural hearing loss (SNHL) is a rare clinical entity accounting for less than 1% of all cases of hearing loss; however, this could be an underestimation based on the absence of specific diagnostic tests [1] and the complexity of differential diagnosis.

☆ All authors declare no conflicts of interest, grants or other founding supports. ⁎ Corresponding author at: Department of Sense Organs, Sapienza University of Rome, Viale dell'Università 31, Roma 00161, Italy. E-mail addresses: [email protected], (P. Mancini), [email protected], (F. Atturo), [email protected], (M. Ralli), [email protected], (M. de Vincentiis), [email protected] (A. Greco).

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Lehnhardt first described an antigen-antibody reaction in patients with progressive bilateral SNHL in 1958. In his report, based on 9/13 patients who developed subsequent involvement of the contralateral ear, he suggested the possibility that an injury to the inner ear might have sensitized the body to a cochlear antigen [2]. In 1979, McCabe described one patient from a series of 18 with idiopathic bilateral progressive SNHL responsive to steroids, proposing the term autoimmune SNHL. In his description, the characteristic onset of the hearing loss was the preeminent factor that led to the diagnosis of autoimmune inner ear diseases (AIED): “a period of progression of the deafness over weeks or months, not hours nor days nor years” [3], therefore excluding from this diagnosis the most important differential causes of SNHL, that are sudden hearing loss and presbycusis. He also described varying degrees of vestibular

https://doi.org/10.1016/j.autrev.2018.01.014 1568-9972/© 2018 Elsevier B.V. All rights reserved.

Please cite this article as: Mancini P, et al, Hearing loss in autoimmune disorders: Prevalence and therapeutic options, Autoimmun Rev (2018), https://doi.org/10.1016/j.autrev.2018.01.014

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P. Mancini et al. / Autoimmunity Reviews xxx (2018) xxx–xxx

dysfunction. In some patients, the involvement of vestibular function is very significant, similar to that of Meniere's disease, which for other authors should be identified as autoimmune inner ear hydrops [4]. However, in some cases, the progression of hearing loss and the manifestation within a more complex clinical picture can differ between patients: in some subjects, it can be bilateral sequential or sudden, and in others the hearing loss can represent the first manifestation of a systemic disorder [5–7]. The definition of autoimmune SNHL varied over decades. Hughes et al. [8] divided primary AIED where the immune response was only direct to the ear, from secondary AIED in case of systemic pathologies, considering that in 30% of cases immune-mediated SNHL may be associated with systemic autoimmune diseases. Aftab et al. [9] proposed the definition “autoimmune inner ear disease” when the pathology is restricted to the ear, whilst for cases of systemic autoimmune disease he preferred to name it “immune-mediated inner ear disease” or “secondary AIED”. Malik et al. [10] proposed the term “immune-mediated inner ear disease” (IMIED) for all cases, distinguishing between “organ-specific” (OS-IMIED) and “systemic” (S-IMIED) forms (Fig. 1). For the purpose of this review, on the light of the consideration that some organ specific autoimmune disorders might be only the initial manifestation of a more systemic disease, we will adopt the definition proposed by Malik. 2. Incidence and prevalence of systemic autoimmune inner ear disease Although the incidence is controversial, S-IMIED is probably more frequent. The audio-vestibular involvement in several systemic autoimmune disorders has been reported by various authors [11–22]. However, incidence of involvement of the inner ear in S-IMIED has been described rarely, whilst prevalence was reported more frequently

[8,23] (Fig. 2). In particular, SNHL has been described in association with the following systemic autoimmune disorders: 2.1 Systemic sclerosis (SS) is a disease characterized by excessive thickening of connective tissue and deposition of extracellular matrix proteins in different organs and tissues, and is more common in women [24]. Its etiology is unknown, but it is known to involve disorders of collagen synthesis as well as vascular and immune system abnormalities. Two clinical forms have been established: the limited and the diffuse variants [25]. The prevalence of hearing loss has been described as ranging from 20 to 77% [26], but no differentiation has been given between variants. The type of hearing loss can be sensorineural, mixed or conductive. A prevalence of SNHL has been reported between 20% [27] to 27% of patients [14]. 2.2 Rheumatoid arthritis (RA) is a chronic, inflammatory disease characterized mainly by cardinal articular and periarticular features, but can involve other organs including heart, lung, skin, and eyes. The auditory system can be affected by a variety of pathologies in the course of the disease. SNHL is the most common type of hearing impairment in RA patients ranging from 25% to 72% [28]. Different causes have been reported for the SNHL in RA, such as auditory neuropathy probably due to vasculitis, and destruction of the cochlear hair cells due to immune complex deposition. Drug-induced ototoxicity was also involved [29]. However, in a recent study by Rahne et al. [30], RA patients seem to be at low risk of disease-associated hearing loss in comparison to other immunological diseases. 2.3 Hashimoto's thyroiditis (HT) is a common autoimmune disease characterized by an elevated concentration of anti-thyroid antibodies. Whilst the exact cause of the disease is not known, the interaction between genetic susceptibility and environmental factors is thought to trigger thyroid autoimmunity [31]. Hearing

Fig. 1. Hearing loss in Systemic Immune-Mediated Inner Ear Disorders (S-IMIED). Dot size reflects prevalence.



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Fig. 2. Diagram indicating prevalence (%) of hearing loss in Immune-Mediated Inner Ear Disorders (IMIED). IMIED is a rare entity accounting for less than 1% of all cases of hearing impairment. Special attention is given to Systemic-IMIED, indicating the autoimmune disorders that may lead to severe to profound sensorineural hearing loss which can benefit from a cochlear implant (within red-dotted line). n/a: only case reports are available in literature, prevalence cannot be reliably determined.

function is impaired in HT patients although a clear incidence and prevalence has not been described. Thyroid autoimmunity seems to have an important impact on hearing loss, particularly at lower frequencies [32], although a clear prevalence was not described. In pediatric HT patients, poor cochlear activity has been shown through distortion products of otoacoustic emissions [33]. 2.4 Sjögren's syndrome (SS) represents a multisystem autoimmune disease characterized by ocular and oral dryness secondary to lymphocytic infiltration and destruction of lacrimal and salivary exocrine glands [34]. An association between SNHL and primary SS was found primarily in very high frequencies [35]. Tumiati et al. [36] reported a prevalence of 46% of SNHL in patients affected by Sjögren's syndrome.

2.5 Mixed cryoglobulinemia (MC) is a rare disorder characterized by the presence of cryoglobulins in the blood. Cryoglobulins are abnormal proteins that become insoluble at reduced temperatures. Damage or inflammation of affected blood vessels and surrounding tissue can develop configuring a pattern of vasculitis. Small blood vessels are usually affected [37]. Probably the immune complex-mediated microvascular involvement of the labyrinthine vessels may be responsible for inner ear damage, determining both audiological and vestibular symptoms. Bilateral SNHL has been found in 22% of patients [15]. 2.6 Systemic lupus erythematosus (SLE) primarily affects women between 15 and 50 and might cause secondary vasculitis [38]. SNHL has been observed with relative frequency in patients with


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SLE, and both autoimmune and vascular mechanisms have been involved in its pathogenesis [39]. The reported prevalence of SNHL ranges from 6% to 70%. [11,40–46]. Sudden SNHL has been also reported in SLE patients with high titer of anticardiolipin antibodies [47–49]. Antiphospholipid antibody syndrome (APS) is an acquired autoimmune disorder characterized by a hypercoagulable state caused by antiphospholipid antibodies. It is defined by the presence of antiphospholipid antibodies in association with recurrent arterial and/or venous thrombosis. In pregnancy, it a possible cause of recurrent spontaneous abortions. APS occurs in isolation (primary APS) or in association with connective tissue diseases (secondary APS), particularly with SLE. There are no studies in literature about SNHL incidence or prevalence in primary APS, with the exception of few case reports. Both unilateral [50–52] and bilateral [53–56] sudden SNHL have been reported. The mechanism of hearing loss in primary APS is not clear: it has been suggested that the clinical manifestation originated in a thrombosis of the labyrinthine vessels [51], induced by the presence of antiphospholipid antibodies [57]. Behcet's syndrome (BS) is a multi-systemic, chronic and recurrent disease characterized by oral thrush and, occasionally, genital sores, uveitis, skin lesions and neurological, vascular and gastrointestinal manifestations with a pathological substrate of leukocytoclastic or lymphocytic vasculitis, mainly from capillaries and venules [58]. Auditory manifestations such as sudden deafness have been described, as well as vertigo during the course of the disease and in relapses [59]. SNHL has been reported in a percentage between 30% [60] and 63% [61]. Giant Cell Arteritis (GCA) is a multi-systemic vasculitis occurring in elder subjects. It mainly involves large and medium-sized blood vessels [62,63]. The first description of deafness in GCA has been provided by Cooke et al. in 1946, who described patients developing unilateral, and subsequently bilateral deafness which improved spontaneously [64]. A later study found that 5 out of 68 patients with GCA had bilateral sensorineural deafness, which did not improve after steroid therapy, with a prevalence corresponding to 7.3% [65]. On the contrary, in a series of 44 patients with GCA, the audiometric tests (pure-tone audiometry) at the time of diagnosis showed a remarkable auditory dysfunction in all patients [66]. In some patients, progressive hearing loss can be an initial manifestation of GCA [65]. During follow-up, improvement in auditory function was observed in 27% of the cases within the first 3 months after the onset of therapy. In addition, despite corticosteroid therapy, further deterioration in auditory function after 3 months of treatment was detected in 3 patients [66]. Wegener's granulomatosis (WG) is defined as a granulomatous inflammation that affects the airways combined with necrotizing phenomena [67]. Apart from the known hearing loss secondary to obstruction of the Eustachian tube due to granulomas in the nasopharynx, a series of 21 patients described sudden SNHL and tinnitus [68]. SNHL was observed only for low frequencies, indicating an increasing stiffness of the basilar membrane with disease duration [69,70]. SNHL has been reported in a percentage between 8 and 63% of patients diagnosed with Wegener's disease [71–73]. Cogan syndrome (CS) has a well-known association with inner ear pathology, and is characterized by fluctuating hearing loss, tinnitus, spontaneous sudden vertigo, and interstitial keratitis [74,75]. Sudden hearing loss has also been described [76]. However, the reported damage is so severe that it does not seem to be the result of a true vasculitis, but rather of a primary labyrinthitis [77]. Despite this finding, a recent paper has shown evidence that vasculitis cannot be excluded as H&E histopathology and anti-CD45 immunostaining of vessels both in the

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auditory and vestibular systems underlying the evidence of vasculitis phenomena in the inner ear [78]. Profound SNHL has been reported in approximately half of the patients with CS resulting in candidacy for cochlear implantation in some patients [79]. In a French nationwide retrospective study of patients with Cogan's syndrome, bilateral hearing loss has been found in 41% of subjects with a prevalence of 31% of severe/profound hearing loss. Polyarteritis nodosa (PAN) is a systemic vasculitis affecting mainly the small and medium-sized arteries, causing segmental necrosis and inflammatory changes in the arterial wall. It involves arteries throughout the body, in particular of the kidney, skeletal muscles, skin, heart and central nervous system [80]. The nature of the hearing loss in PAN can be conductive, mixed or sensorineural. SNHL is usually bilateral and symmetrical. It may have a sudden onset or a rapidly progressive course [81–85]. In a patient whose first manifestation of the disease was sudden unilateral deafness and vertigo, the temporal bone histopathological study showed atrophy of the stria vascularis, a bilateral cochlear condition in the form of loss of the organ of Corti in various portions of the cochlea, the absence of the tectorial membrane, whereas no vestibular histopathological changes were observed [86]. In another patient with a diagnosis of PAN and unilateral profound hearing loss and vertigo, the histopathological study found vasculitis in the internal auditory artery, accompanied by ossification of the cochlea and the vestibular system as well as endolymphatic hydrops in the basal ramp of the cochlea [87]. An estimation of hearing loss prevalence in PAN is not possible because of the scarcity of reported cases. Relapsing polychondritis (RP) is an autoimmune disease that affects, unilaterally or bilaterally, the cartilage of the ear, nose and trachea [88]. Hearing loss and vertigo have been described in RP and pathophysiology has been explained assuming the existence of a vasculitis of the labyrinthine artery and its branches [89]. Hearing loss, which might be either conductive or sensorineural, has been demonstrated in as many as 46% of patients with RP [90]. Profound hearing loss seems to be rare in RP [91,92]. Takayasu's arteritis (TA) primarily affects young people, especially women between 15 and 25 years. In this vasculitis affecting large vessels, a patient has been described who presented sudden deafness and decreased pulse in the radial artery. The hearing condition worsened upon withdrawal of parenterally administered steroids and improved when they were reintroduced [93]. Hearing loss has been rarely reported in patients with TA [94–97]. Vogt-Koyanagi-Harada's disease (VKH) is a systemic autoimmune disorder characterized by the destruction of melanocytes by T-lymphocytes resulting in the inflammation of organs containing pigment [98,99]. It causes granulomatous uveitis accompanied by neurologic and auditory-vestibular symptoms. Auditory and vestibular manifestations of the disease are observed in up to 2/3 of patients and typically include bilateral, rapidly progressive, SNHL, tinnitus, and vertigo [100–102]. Dousary [100] conducted a retrospective review of 24 VKH cases and described auditory-vestibular symptoms in a number of participants, including hearing loss (50%), tinnitus (42%), and vertigo (17%). Pyoderma gangrenosum (PG) is a condition characterized by the presence of necrotic ulcers often with a bluish undermined margin. These may occur anywhere on the body and may spread rapidly to cover large areas. At least half of all patients with pyoderma gangrenosum are found to have ulcerative colitis [103]. Pyoderma gangrenosum seems to be a form of vasculitis: the involvement of immune complexes may be the trigger for the production of lesions [104]. Few cases of SNHL have been reported in PG [105], whilst several cases of sensorineural deafness associated with ulcerative colitis have been reported [106,107].



2.17 Ulcerative colitis (UC). Summers and Harker [108] described the first case of dysacusis associated with ulcerative colitis in 1982. Since then other cases have been reported, including progressive bilateral and sudden SNHL [109–116]. In a retrospective study, SNHL was found in less than 2% of 57 adult patients with ulcerative colitis [117]. Even though hearing thresholds may be within normal limits, decreased distortion product otoacoustic emission amplitude values might indicate a cochlear involvement in UC patients [118].

3. Therapeutic approaches to hearing loss In the absence of a reliable marker for IMIED, the disease is defined by an appropriate clinical presentation, by exclusion of other known causes of SNHL and by a positive response to steroid therapy. Response to steroids has been a requisite clinical criterion for diagnosis [119]. Currently, the management of IMIED is aimed at hearing preservation. Pharmacological treatment is limited mainly to high-dose corticosteroids with prolonged taper and low-dose maintenance therapy. The most widely used regimen is an empiric treatment protocol proposed by Rauch et al. [120]: initial therapy in adults is a 60 mg/day or 1 mg/kg/day therapeutic trial of prednisone for 4 weeks, followed by maintenance dose of 10 mg for a total treatment of at least 6 months. Although an initial clinical response to steroids has helped to define the diagnosis, for those with progressive hearing loss requiring corticosteroid treatment, only 14% remain responsive after 34 months [121]. A response rate of 60% to steroids has been reported previously [120]. Moreover steroid-associated side-effects occur in 15% of patients during the first month of treatment and 6% have to discontinue steroid therapy [122]. Several strategies have been proposed to overcome this problem, such as shorter steroid regimes [123] that might be associated with a higher rate of relapse, or intratympanic steroid injections. Intratympanic glucocorticoid therapy delivers a higher intralabyrinthine concentration whilst eliminating systemic side effects. In steroid-responsive cases, intratympanic glucocorticoids may restore and maintain function with serial treatments [124], even though the evidence supporting its use in IMIED is limited. Intratympanic steroid injections have been tested in IMIED patients refractory to steroids [125]. Those patients receiving weekly injections of 6-methylprednisolone for 2 months and 68% of them showed hearing improvement with significant reduction of vestibular symptoms. Alternative immunosuppressive strategies were tried in patients who either failed to respond to glucocorticoids or did not maintain functional improvement when therapy was withdrawn. These strategies include the use of methotrexate, cyclophosphamide, azathioprine, tumor necrosis factor antagonists, and plasmapheresis. For the future, the possibility of interventions modulating the immune system directly in the inner ear to repair the tissue organization and improve hearing in patients with SNHL has been speculated. Tissue macrophages in the inner ear appear to be a potential target for modulating the immune response in the inner ear in the pathophysiology of SNHL [126]. However, some patients prefer to avoid or cannot tolerate the side effects of medical therapy. Besides medical therapy in subjects where hearing loss ranges between mild to severe (25–70 dB) rehabilitation with hearing aids could be attempted. There are no studies regarding the application of hearing aids in OS-IMIED and S-IMIED. The main difficulty of hearing aids application in IMIED is represented, in a first stage, by the fluctuation of hearing loss, as in Meniere's disease, and in any degree of hearing loss by distortion of perception linked to cochlear damage. As a matter of fact, in patients affected by Meniere's disease - which has been suspected to have possible origin from autoimmune mechanisms [4] hearing aids are often refused by patients because of poor speech

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recognition scores in the affected ear. Also, these patients require frequent device regulation because of hearing fluctuation and adverse reaction to intense sound linked to distortion of intensity perception typical of cochlear damage (recruitment) [127]. For these reasons, many professionals in the field still do not consider traditional hearing aids as a viable option. There is more recent evidence [128] for better audiological outcomes during the third phase of Meniere's disease, when the hearing loss becomes stable. In this phase hearing aids are better tolerated, although slow adaptation and frequent hearing aid adjustments are needed. It would be natural to infer that in IMIED the response to conventional hearing aid rehabilitation could be similar, although no specific studies have been reported in literature. In patients who develop severe/profound SNHL and who no longer benefit from hearing aid amplification, cochlear implantation is indicated [9]. The incidence of severe/profound hearing loss in autoimmune and immune mediated inner ear diseases is unknown: it has been reported in case reports or “single center” statistics, usually related to cochlear implant (CI) procedure. Bovo et al. [1] found profound hearing loss in 60% of patients suffering from Cogan's Syndrome. In Susac Syndrome, 4,3% of patient developed severe-profound hearing loss [129]. The hearing loss was progressive becoming severe-profound in 22.2% of patients with RP [91], in 2% of patients with Systemic Vasculitis [130] and 4% of patients affected by ulcerative colitis [131] besides few case reports described in Systemic sclerosis [132], Bechet disease [133]. 4. Cochlear implant outcomes in autoimmune disorders Although patients affected by immune-mediated profound SNHL represent ideal candidates for cochlear implantation, as these patients become deaf after years of hearing, the associated systemic disease, the specific damage on inner ear structures and the medication taken may influence the result of cochlear implantation. Malik et al. [10] tried to identify disease- and patient-specific factors associated with CI performance. In this paper, they found that organ (ear) specific immune-mediation, younger age at CI and complete electrode insertion were all factors associated with better speech perception. 4.1 Systemic diseases influence. Differences in CI results between patients with OS-IMIED and S-IMIED have been reported [10]. The authors speculated that the results may depend on the effects of IMIED that are not only confined to the sensory epithelium but may also extend to the spiral ganglion and the fidelity with which the auditory nerve transmits signals to the central nervous system. The damage of anatomical structures in Cogan's syndrome has been described, and consists in the degeneration of spiral ganglion cells, cystic degeneration of the stria vascularis, demyelination of the acoustic nerve, and vasculitis of the internal auditory artery [77,134]. Auditory neuropathy has been described also in systemic sclerosis [132]. Moreover, the systemic autoimmune disease may render patients potentially more susceptible to complications. The relation between autoimmune disease and complications has been widely described in patients with Cogan's syndrome. Among the potential post-operative complications, those related to the flap are reported as the most common [135,136]. Wound healing disorders and recurrent episodes of skin infections [137,138] and pressure sores of the occiput from the post-operative head bandage [139] have also been reported. Skin atrophy from long-term corticosteroid and immunosuppressant therapy and ischemia caused by vasculitis may be considered to be adverse factors contributing to the described flap complications described by Bacciu et al. [140]. Complications related to the flap and infection could be prevented by selecting an appropriate surgical technique, a short suspension of immunosuppressive drugs and intraoperative and postoperative courses of antibiotics, as reported by Quaranta et al. [141].


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4.2 Ossification/pathogenesis influence. It has been suggested that patients with IMIED could have suboptimal implantation outcomes because of the histologic sequelae of the disease on the cochlea. In fact, cochlear implantation in OS-IMIED and S-IMIED has been shown to give good hearing outcomes only when full electrode insertion is accomplished [9,10,137,141]. The complete insertion of the electrode can be influenced by inner ear modification induced by the autoimmune pathology itself. Animal models of IMIED show that inflammatory infiltrates within the cochlea can lead to cochlear fibrosis and calcification. Postmortem analysis of temporal bones of patients affected with IMIED reveals the presence of fibrosis and new bone formation [142]. Such fibrosis can potentially lead to osteoneogenesis similar to that which has been observed in postmeningitic deafness and other inflammatory ear conditions [84,141–146]. de Souza et al. [147] and Xu et al. [148] described the evolution of labyrinthitis ossificans into three stages: acute, fibrous, and ossification. This last stage is characterized by bone formation first observed in the basal turn of the cochlea and can occur as early as two months after onset of inflammation. Benson [146] reported a case of a patient with ulcerative colitis and bilateral profound hearing loss, undergoing CI surgery. During surgery, they found bone obliteration of round window and ossification of the basal turn. He speculated that the process could be activated by a significant autoimmune response that the patient mounted against the labyrinth. As in meningitis, ossification starts from the basal turn, progressively involving the middle and apical turns. The inner ear communicates with systemic immunity via the circulation by the passage of cells through the spiral modiolar vein and its collecting venules in the scala tympani. The spiral modiolar vein appears to play a central role in the movement of cells from the systemic circulation into the inner ear [149]: consequently, the inflammatory response is initiated in the scala tympani. The final outcome of inflammation is often fibrosis and osteoneogenesis: the ossification occurs preferentially within the scala tympani, initially involving the round window and the basal turn. The possibility of fibrosis and ossification in the basal turn of the cochlea has also been reported in Polyarteritis nodosa [150], whilst it has not been described in Vogt-Koyanagi-Harada Disease [151], although only one case report has been reported. Inner-ear obliteration has been described in ulcerative colitis patients [115]. Ossification has been described also in a specific systemic vasculitis [141]. Cochlear fibrosis or ossification has been found to affect up to 50% of implanted ears in patients suffering from autoimmune and immune-mediated SNHL [9], so that in appropriate candidates, earlier implantation may be indicated before postinflammatory obliterative changes in the cochlea. For the same reason, other authors claimed that the restoration of hearing via cochlear implantation may be appropriate earlier rather than later [10,141]. Although an early approach to the cochlea may let the electrode insertion easier, the long-term follow-up results are not always predictable. In one patient, Bovo et al. [1] reported a progression of cochlear ossification after implantation with four electrodes becoming progressively non-functioning and six electrodes being switched off due to painful sensations. A post-implant deterioration of speech perception was observed in one patient with Cogan's syndrome by Quaranta et al. [141]: it was speculated that the deterioration of hearing after cochlear implantation could be a consequence of apposition or progression of new bone formation, which in turn increases the distance of the electrodes from neural structures. In RP, cochlear implantation was first reported by Seo et al. [152], underlining good hearing results after a short-term (3 months) follow-up. However, cochlear fibrosis/ossification and deterioration of previously excellent hearing performance have been described [92].

Hence, when performing cochlear implantation in S-IMIED, it is important to consider that the autoimmune disease may induce deterioration of performance with CI due to local relapsing inflammatory responses 5. Discussion At present, both OS- and S-IMIED represent a diagnostic challenge for clinicians. The scarcity of these conditions, the high number of differential diagnoses and the absence of reliable markers have forced audiologists to define the disease based on its clinical presentation, exclusion of other known causes, and a positive response to steroid therapy. Therefore, in every patient who has progressive bilateral SNHL with no other explainable cause, the diagnosis of IMIED should be considered, the association with a systemic autoimmune disease evaluated and a trial of corticosteroids attempted [153]. However, the trend in time of hearing loss can be very different between patients. Whilst in the majority of cases the hearing loss is bilateral and progressive, in some cases patients can initially present a sudden unilateral hearing loss, that could be hardly suspected as IMIED, especially in absence of OS-IMIED. Hearing loss can represent the first manifestation of systemic autoimmune disorder: a basic immunologic work-up study could be helpful to identify an aspecific autoimmune response [6,154] and to direct the patient to immunologic assessment. In almost 25% of patients with OS-IMIED, a systemic autoimmune disorder develops during the clinical follow-up [8,19,155]. Also, the enormous variability in the prevalence of hearing loss might depend partially on the reduced numbers and composition of subjects belonging to the study groups in the various research clinics who have tackled this theme. It is not possible to exclude a systemic autoimmune disease, even in the absence of serological markers for autoimmunity. Some patients are persistently negative for disease-specific auto-antibodies, condition defined as seronegative autoimmune diseases [156]. This situation can be related to an effective absence of auto-antibodies, probably because other mechanisms are involved, or to some difficulties in the method of detection. Although the prevalence of seronegative autoimmune diseases is low, they may represent a practical problem for a correct diagnosis. Another problem is the heterogeneity of the systemic diseases that can change over time. A final diagnosis may require many years before becoming clear, and a patient may be diagnosed with a different pathology before the clinical picture becomes evident. Probably this is also the reason for which it is not possible to have clear indications about the incidence and prevalence of SNHL in specific systemic autoimmune disorders. Anyhow, outcome studies have demonstrated excellent results and good performance in implanted IMIED patients, compared with patients with other causes of deafness. Interestingly, regardless of the etiology of the various diseases affecting the inner ear, pathological findings are identical: they include degeneration and destruction of the peripheral receptor; segmental and diffuse infiltration of lymphocytes, plasma cells, and macrophages; proliferation of fibrous tissue; and varying degrees of ossification of the inner ear [157]. The only exception could be the APS, where SNHL could originate from the thrombosis of the labyrinthine vessels [51]. The main problem for good results is the risk of ossification, that could prevent the progression of the electrode into the cochlea or compromise outcomes in subsequent reactivation of the disease. An open issue is the CI performance over time in IMIED: few studies have been conducted with long-term follow up and results seem to be assuring [9,10,141]. However, deterioration of hearing after cochlear implantation, probably due to apposition or progression of new bone formation or local relapsing inflammatory responses has been also described [92]. Probably a better control of the systemic diseases, reducing the autoimmune activity into the cochlea, could help to reduce the deterioration.



Based on this evidence, it could be assumed that surgery should not be postponed in case of severe/profound SNHL diagnosed as IMIED, whilst a timed follow up of intracochlear electrode function should be maintained over time. Further studies with long-term follow ups in cochlear implantees for IMIED could help to give a better understanding of the approach to be taken and of possible outcomes. 6. Conclusion Incidence and prevalence of OS-IMIED and S-IMIED is unclear. Most of the studies in literature are about few cases or single center experience. It could be useful, in order to perform fast diagnoses and to treat adequately SNHL, obtain more data about the epidemiology in different systemic pathologies. To this purpose, prospective studies could be appropriate. Systemic autoimmune disorders sustained by vasculitis process, together with cochlear relapsing inflammation may induce more frequent and more severe deterioration of hearing perception. Cochlear fibrosis or ossification has been found to affect up to 50% of subjects, mainly caused by segmental and diffuse infiltration of lymphocytes, plasma cells, and macrophages, and proliferation of fibrous tissue. Early diagnosis and immediate therapeutic approach, could give better results. In case of severe/ profound deafness an earlier implantation may be indicated before post-inflammatory obliterative changes in the cochlea. References [1] Bovo R, Aimoni C, Martini A. Immune-mediated inner ear disease. Acta Otolaryngol 2006;126:1012–21. [2] Lehnhardt E. Sudden hearing disorders occurring simultaneously or successively on both sides. Z Laryngol Rhinol Otol 1958;37:1–16. [3] McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 1979;88:585–9. [4] Greco A, Gallo A, Fusconi M, Marinelli C, Macri GF, de Vincentiis M. Meniere's disease might be an autoimmune condition? Autoimmun Rev 2012 Aug;11(10): 731–8. [5] Vos FI, Merkus P, van Nieuwkerk EB, Hensen EF. Rare cause of bilateral sudden deafness. BMJ Case Rep 2016 Oct 8;2016. [6] Atturo F, Colangeli R, Bandiera G, Barbara M, Monini S. Can unilateral, progressive or sudden hearing loss be immune-mediated in origin? Acta Otolaryngol 2017 Aug;137(8):823–8. [7] Rossini BAA, Penido NO, Munhoz MSL, Bogaz EA, Curi RS. Sudden Sensorioneural hearing loss and autoimmune systemic diseases. Int Arch Otorhinolaryngol 2017 Jul;21(3):213–23. [8] Hughes GB, Kinney SE, Barna BP, et al. Practical versus theoretical management of autoimmune inner ear disease. Laryngoscope 1984;94:758–67. [9] Aftab S, Semaan MT, Murray GS, Megerian CA. Cochlear implantation outcomes in patients with autoimmune and immune-mediated inner ear disease. Otol Neurotol 2010 Oct;31(8):1337–42. [10] Malik MU, Pandian V, Masood H, Diaz DA, Varela V, Dávalos-Balderas AJ, et al. Spectrum of immune-mediated inner ear disease and cochlear implant results. Laryngoscope 2012 Nov;122(11):2557–62. [11] Andonopoulos AP, Naxakis S, Goumas P, Lygatsikas C. Sensorineural hearing disorders in systemic lupus erythematosus. A controlled study. Clin Exp Rheumatol 1995;13:137–41. [12] Berrettini S, Bruschini E, Sellari-Franceschini S, Segnini G, Bernardini M. Interessamento dell'orecchio interno nelle malattie sistemiche sostenute da disordini immunologici. Audiologia Italiana 1989;6:385–402. [13] Berrettini S, Tavoni A, Sellari-Franceschini S, et al. Interessamento dell'orecchio interno nel Lupus Eritematoso Sistemico. Audiologia Italiana 1989;6:428–32. [14] Berrettini S, Ferri C, Pitaro N, Bruschini P, Latorraca A, Sellari-Franceschini S, et al. Audiovestibular involvement in systemic sclerosis. ORL J Otorhinolaryngol Relat Spec 1994 Jul–Aug;56(4):195–8. [15] Berrettini S, Ferri C, La Civita L, Segnini G, Lombardini F, Bruschini P, et al. Inner ear involvement in mixed cryoglobulinaemia patients. Br J Rheumatol 1995;34(4):370. [16] Gemignani G, Berrettini S, Bruscini R, et al. Hearing and vestibular disturbances in Behcet's syndrome. Ann Otol Rhinol Laryngol 1991;100:459–63. [17] Harris JR, Ryan AE. Fundamental immune mechanisms of the brain and inner ear. Otolaryngol Head Neck Surg 1995;112:639–53. [18] Magaro M, Zoti A, Altomonte L, et al. Sensorineural hearing loss in rheumatoid arthritis. Clin Exp Rhenmatol 1990;8:487–90. [19] McCabe BE. Autoimmune inner ear disease. In: Bernstein J, Ogra P, editors. Immunology of the ear. New York, NY: Raven Press; 1987. [20] Mondain M. Surdités auto-immunes: mythe ou réalité? Les Cahiers d'ORL 1994; 39:309–17. [21] Stephens SDG, Lnxon L, Hinchcliffe R. Immunological disorders and auditory lesions. Audiology 1982;21:128. [22] Sundel RP, Cleveland SS, Beiser AS, et al. Audiological profiles of children with Kawasaki disease. Am J Otol 1992;13:512–5.

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