Clinical manifestations

Presentation and course

Autoimmune sensorineural hearing loss characteristically presents as an asymmetrical bilateral progressive sensorineural hearing loss frequently accompanied by vestibular symptoms. The temporal progression can range from acute (developing from several hours to 3 days) to a chronic progressive form (developing more slowly over several months). The typical time frame is between these two extremes, presenting as a rapidly progressive and often fluctuating bilateral sensorineural hearing loss, evolving over weeks to months (11). This usually involves high frequencies and results in a down-sloping audiogram. Less commonly, a low-frequency loss has been reported, particularly in patients with lupus (85; 130). Although it is bilateral in up to 80% of cases, unilateral presentations also occur (47). The presence of other immune diseases is also common, with as many as 30% of patients exhibiting some form of systemic immune-related disease (47). Autoimmune hearing loss can be precipitated by treatment with immune checkpoint inhibitors, which activate the immune system to fight the underlying cancer but then are associated with an increased frequency of autoimmune disorders (91).

In addition to complaints of hearing loss, nearly half of patients with autoimmune sensorineural hearing loss report other audiovestibular symptoms, including aural fullness, tinnitus, lightheadedness, and vertigo (47). Facial nerve palsy is also observed occasionally (72). Although the age of presentation is variable, the mean presentation is in the fifth decade, with females making up one to two thirds of autoimmune sensorineural hearing loss cases. This increased prevalence among middle-aged females seen in some studies is consistent with other autoimmune disorders (47). The incidence of autoimmune sensorineural hearing loss is thought to constitute less than 1% of all cases of hearing impairment with dizziness.

Cogan syndrome is characterized by a mix of audiovestibular symptoms and inflammatory ocular disease, occurring concomitantly or within 6 months of each other. This is usually a relapsing condition (29). There can be multisystem involvement (55). Typical ocular symptoms consist of acute unilateral or bilateral interstitial keratitis. Audiovestibular symptoms include Meniere-like attacks of severe vertigo, nausea, ataxia, oscillopsia, tinnitus, and fluctuating, progressive hearing loss (29). Audiovestibular dysfunction leads to progressive hearing loss and deafness in 60% of patients (44).

Clinical vignette

Case 1. An otherwise healthy 28-year-old black man presented with a complaint of hearing loss in his right ear for several weeks’ duration. He had mild disequilibrium but no vertigo or tinnitus. Physical examination was normal. Audiometric analysis revealed an asymmetric, moderate-to-severe sensorineural hearing loss in his right ear with a speech discrimination score of 72%. Blood studies, including a syphilis assay, were normal, and MRI with gadolinium revealed no retrocochlear pathology. The patient was given a prescription for methylprednisolone but did not comply with the medication and was lost to follow-up. He returned 18 months later with complaints of worsening hearing in his left ear and intermittent disequilibrium. Audiogram revealed persistence of his previous right-sided sensorineural hearing loss and interval development of moderate (40 dB) left-sided sensorineural hearing loss with a speech discrimination score of 80%. Electrocochleography and electronystagmography were normal. He was started immediately on a 4-week course of prednisone 60 mg/day. Follow-up audiogram at 4 weeks showed improvement in his pure tone thresholds and speech discrimination. Twelve-week follow-up revealed a residual mild loss in the left ear. The patient has been off immunosuppressive therapy for 6 months with no further change in his hearing and no vestibular symptoms.

Case 2: Susac syndrome with livedo reticularis and autoimmune sensorineural hearing loss (105). A 45-year-old, previously healthy man presented with subacute hearing loss, blurry vision, headaches, intermittent confusion, and a truncal rash. He was afebrile and had a normal mental status examination. With prescription lenses, visual acuity was 20/20 in both eyes, but peripheral vision was impaired in both eyes. Fundoscopic examination revealed bilateral retinal flame hemorrhages and cotton wool spots. A diffuse, nontender, and blanchable rash was present on the abdomen and flank.

Blood studies were unrevealing, including a comprehensive metabolic panel, complete blood count, and PCR test for SARS-CoV-2 RNA. Inflammatory markers and serum autoimmune antibody panel, including C-reactive protein, erythrocyte sedimentation rate, antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, and cyclic citrullinated peptide, were also negative.

MRI of the brain without and with contrast showed significant hyperintensities in the white matter throughout the rostrum, genu, and body of the corpus callosum.

Cerebral angiography revealed no large vessel occlusion.

The patient underwent an audiogram, which revealed moderate unilateral biphasic sensorineural hearing loss in the right ear. The audiogram revealed moderate sensorineural hearing loss at 500 Hz, rising to within normal limits at 750 to 2000 Hz. Moderate sensorineural hearing loss was also recorded at 4000 to 8000 Hz in the right ear.

CSF studies were significant for elevated protein (273 mg/dL; normal range 15-45 mg/dL), albumin (207 mg/dL; normal range 0-35 mg/dL), immunoglobulin G (31.4 mg/dL; normal range 0-6 mg/dL), and IgG synthesis rate (47.0 mg/d; reference range < 8.0). A comprehensive autoimmune and infectious panel of the CSF was unremarkable.

A punch biopsy of the left flank revealed mild perivascular lymphocytic infiltrate, vascular congestion, and focal vascular ectasia consistent with livedo reticularis.

Susac syndrome was diagnosed, and proposed pathogenic mechanisms of Susac syndrome were reviewed; pathophysiological mechanisms of livedo racemosa and livedo reticularis were contrasted.

Intravenous methylprednisolone (1 g daily for 5 days) and rituximab infusion were started, but rituximab was discontinued due to persistent tachycardia and the development of atrial fibrillation with a rapid ventricular response. Subsequently, cyclophosphamide (1 g) was administered with mesna (ie, a detoxifying agent used to prevent hemorrhagic cystitis). He was discharged on a tapering dose of oral prednisone. At a 2-week follow-up appointment, he received another infusion of cyclophosphamide. His rash resolved, he had no further episodes of encephalopathy, and hearing and peripheral vision both improved.

Case 3: autoimmune sensorineural hearing loss and type 1 autoimmune hepatitis (131). A 60-year-old man was initially hospitalized for low-grade fever, slightly raised erythematous lesions, and asymmetric ankle swelling. C-reactive protein (156 mg/L; reference range < 6 mg/L), erythrocyte sedimentation rate (69 mm/h; reference range 0-30 mm/h), and liver enzymes were elevated.

Tests for hepatitis (A, B, and C), rheumatoid factor, anti-cyclic citrullinated peptide antibody, iron, ferritin, ceruloplasmin, and angiotensin-converting enzyme were normal. A chest x-ray did not reveal hilar adenopathy or pulmonary infiltrates. Symptoms abated substantially with empiric cefuroxime for a presumptive diagnosis of possible erysipelas.

Two weeks later, he was readmitted for recurrent fever, weight loss, and low back pain. No source of sepsis was found. Laboratory testing showed normochromic, normocytic anemia, leukocytosis, and elevated ESR, CRP, and liver enzymes. Repeat blood cultures, urine culture, microbial serology, and echocardiography were all negative. Because MRI was contraindicated (due to a metallic foreign body after surgery), three-phase scintigraphy and CT scan were done and showed possible sacroiliitis in the left sacroiliac joint (attributed to his congenital right hip dislocation and associated pelvic dysplasia but nevertheless treated as possible septic arthritis). CT of the chest and abdomen revealed mild fibrous elements in the upper lobes of the lungs, but no bile duct stenosis was evident, and the liver was homogenous without focal lesions. A Mantoux test was negative. Fever persisted for more than a week, and liver enzymes and acute-phase reactants remained elevated, so the initial antibiotic treatment was discontinued, and piperacillin-tazobactam and linezolid were started. Two weeks later, the symptoms gradually improved, and the patient was discharged home on a regimen of oral ciprofloxacin and clindamycin, but ESR and liver enzymes remained elevated. Blood tests were positive for antinuclear antibodies (1:160) with a speckled pattern. Anti-double-stranded DNA, anti-Sm, anti-Ro/SSA, anti-La/SSB, anti-RNP, anti-ribosomal P, and antiphospholipid antibodies were all negative. Repeat CT showed no abnormal findings in the left sacroiliac joint.

Four months later, he developed sudden hearing loss and tinnitus with aural fullness in the left ear. Oral corticosteroids were empirically administered for 5 days, but because the symptoms persisted, the patient was readmitted. Neurologic examination and otoscopic findings were normal. Weber test lateralized to the right, consistent with left sensorineural hearing loss. An audiogram showed normal hearing thresholds on the right and profound sensorineural hearing loss on the left.

Intravenous methylprednisolone (250 mg daily for 4 days and a gradual taper thereafter) was begun to treat the profound left sensorineural hearing loss. A liver biopsy was performed because of the considerable and persistent elevation of transaminases and enzymes associated with cholestasis. Smooth muscle antibodies (1:40) and perinuclear antineutrophil cytoplasmic antibodies (1:80) were elevated, but antimitochondrial antibodies were negative. Symptoms stabilized, and the patient was discharged home.

Three days later, he was again readmitted because of new hearing loss and tinnitus in the right ear as well as difficulty understanding conversations amid background noise. A repeat audiogram revealed moderate right sensorineural hearing loss.

Brainstem auditory evoked responses showed findings consistent with asymmetric, bilateral sensorineural hearing loss. CRP and liver tests remained elevated. Brain CT was normal, and high-resolution CT of the temporal bones revealed no lytic findings or erosions. Because of his devastating bilateral sensorineural hearing loss, he received three intratympanic dexamethasone injections in both ears. The liver biopsy revealed lymphocytic inflammatory infiltration of the portal tract and mild findings of non-alcoholic fatty liver disease without hepatic fibrosis or histopathological demonstration of granuloma.

Various other autoantibody tests were obtained, but these were unrevealing except for p-ANCA (1:80 with positive titers > 1:20) and SMA directed against filamentous actin (1:160 with positive titer > 1:40).

As shown on a third audiogram approximately 2 months after the initiation of oral treatment, hearing acuity improved in the right ear by approximately 20 dB after three intratympanic dexamethasone injections followed by a course of intravenous methylprednisolone (500 mg/d x 3 days).

Oral prednisolone with azathioprine was subsequently started.

Biological basis

Etiology and pathogenesis

Table 1. Diseases Associated with Autoimmune Sensorineural Hearing Loss

Although the exact etiology of autoimmune sensorineural hearing loss is unknown, a proposed pathogenic mechanism of autoimmune sensorineural hearing loss involves inflammation and an immune-mediated attack of specific inner ear structures, leading to an excessive Th1 immune response (ie, involving the Th1 subset of T helper cells and producing Th1-type cytokines) with resultant vascular changes and tissue damage in the cochlea (32). Controversy exists as to whether the inner ear is targeted directly through a cell-mediated immune response or whether the damage results from a humoral immune complex destruction of key inner-ear structures. Viral, vascular (ie, microthrombosis), immunologic (eg, immune-complex deposition), and electrochemical (eg, through disruption of neurosignaling) mechanisms have all received consideration (33; 32).

Immunology and molecular biology advances have helped identify serum antibodies directed against several inner-ear antigens in many patients with the disorder. Similarly, experimental models show immune-mediated damage to key inner-ear structures such as the stria vascularis. The possibility that injury to inner-ear structures results from a localized immune response directed against the inner ear or from systemic immune responses with limited target organs remains controversial.

Once thought to be an immunologically privileged site, the inner ear is much more responsive to immune stimulation than the brain and acts as an afferent limb of the immune pathway (38). Both humoral and cell-mediated responses are established for inner-ear tissues and fluids and help to protect these vital structures from infection (42). However, this immune response and resultant inflammation can result in serious injury to the delicate cochlea and vestibular tissues. Researchers propose that with the early inflammatory process, inner-ear tissue up-regulates expression of adhesion molecules, such as ICAM-1, thus, permitting the movement of inflammatory cells into the labyrinth (108).

However, direct evidence of immune-mediated damage to inner-ear structures is not easily demonstrated. The first successful induction of autoimmune sensorineural hearing loss and vestibular disease in rats was accomplished by immunizing the rats with type II collagen, an extracellular matrix protein found throughout the inner ear. Histological analysis of inner ears from these animals demonstrated significantly greater perivascular inflammation and immune complex deposition compared with control animals. Similar experiments with a guinea pig model produced injury to the stria vascularis, organ of Corti, and spiral ganglion cells (125).

Subsequent clinical studies used type II collagen as the antigen for lymphocyte transformation tests and found positive responses in half of the patients (34 of 68) with progressive sensorineural hearing loss compared to only 6% (4 of 68) in controls (07). Additional work using Western blot assays found anti-type II collagen antibodies in 12 of 21 patients with various forms of inner-ear disease. Anti-type IX collagen (specific for the labyrinthine membrane and tectorial membrane) was detected in 13 of 21 blots (51). Animal models have been developed utilizing type II (126) and type IX collagen (15) as well as the myelin P0 protein (68) and tubulin (127). Other authors suggested that at least one other, and perhaps several other, antigens are targets for the immune response (42). Investigators previously reported on a 68-kDa antigen, which was thought to represent heat shock protein 70 (HSP70), identified in the serum of patients with progressive hearing loss suspected to be immune-related (10). However, the identity of this antigen has been called into question in several subsequent studies (124; 80). Mice carrying the Kresge Hearing Research Institute-3 (KHRI-3) antibody developed hearing loss (81); the responsible inner-ear antigen was found to be human choline transporter-like protein 2 (CTL2). Choline plays a central role in the biosynthesis of acetylcholine, an inner-ear neurotransmitter, and is a major component of cell membranes in the form of phosphatidylcholine. Current theories suggest that the CTL2 complex is essential for hair cell survival. In conclusion, there is mounting evidence that the target antigen of the 68-kDa antibody is not HSP70 but is likely CTL2.

Another debate concerns whether the ear is directly affected by specific antibodies against sensory structures or indirectly injured by elevated levels of immune complexes from a systemic disease process. The systemic disease explanation maintains that there is exposure of normally sequestered inner-ear antigens that drive an immune response. The inner ear has its own immune system, comprised of immunocompetent cells and antibody trafficking (37). Once the inner ear has become activated, new cells either form or enter from the systemic circulation, penetrating the blood-labyrinthine barrier. In both humans and animals, macrophages, B cells, and T cells can enter the peri-saccular space (37; 03). Blood vessels of the spiral modiolar vein, adjacent to the scala tympani, serve as the initial site of lymphocyte entry into the inner ear. As early as 6 hours after stimulation, immune cells begin to accumulate around the blood vessels within the spiral modiolar vein and then begin to enter the scala tympani (39). Control of this process is not well understood. Ablation of the endolymphatic sac reduces immune responses in the cochlea (Tomiyama and 38). This process leads to the production of IL-2. IL-2 is normally absent from the perilymph in the resting state, but post-stimulation levels peak approximately 18 hours after stimulation and then decline over a subsequent 5-day period, well in accordance with entry of helper T cells and macrophages. Furthermore, mediators such as ICAM-1 reach their maximum level on the epithelium of the spiral modiolar vein and collecting venules by day 2 and gradually diminish. IgG, IgA, and IgM immunoglobulins have been demonstrated in both human and animal perilymph, but their origin remains to be elucidated (123). Several studies have also demonstrated the presence of IgG immune complex deposits within strial capillaries and extracapillary spaces. These findings accompany marked intercellular edema and capillary basement membrane thickening (58; 75; 122; 82; 62). The studies suggest that immune-mediated injury of stria vascularis may represent a primary injury.

Beyond the cellular mediators of inflammation, attention has been focused on the cytokines involved in this process. Besides elevation of IL-2, multiple studies have reported elevated levels of TNF-alpha in animal models. On binding to its receptor, TNF-alpha triggers expression of cell adhesion molecules on vascular endothelial cells, facilitation of leukocyte and monocyte extravasation, and recruitment to the site of inflammation. In the KLH model of autoimmune inner-ear disease, TNF-alpha is the first cytokine expressed by inner-ear-infiltrating cells following systemic KLH-antigen immunization and infusion into the cochlea (99). Etanercept, a TNF-alpha antagonist, reduced cell infiltration and cochlear fibrosis compared to controls (88). Similar results were obtained with intraperitoneal etanercept injection in the same model (119). Finally, cells within the endolymphatic sac are required for developing an adaptive immune response and are a source of TNF-alpha, needed for amplification of the immune response in the KLH model (100). Apparently, continuous antigen exposure can lead to a chronic inflammatory cascade that results in damage to the sensitive structure of the inner ear. Interleukin-1 is an important cytokine in the immune system activating multiple cell types and is elevated in corticosteroid-resistant patients. Treatment with interleukin-1 inhibitors can improve hearing loss in these patients. Interestingly, although the interleukin-1 decay receptor is induced in corticosteroid-responsive patients, suggesting a decrease in interleukin-1 signaling, treatment with interleukin-1 blockade in those patients produced only a modest change in hearing, suggesting that separate disease processes are involved (112).

An association of autoimmune sensorineural hearing loss with antiphospholipid antibodies (ie, anti-cardiolipin and anti-beta-2-glycoprotein-1) has also been suggested, but this has not been validated in larger cohorts (79; 61). These antibodies are seen in the setting of SLE, myriad autoimmune states, and in isolation. They are associated with a hypercoagulable state. Their exact relationship to sensorineural autoimmune hearing loss is unclear. Antinuclear antibody has also been found at a higher rate in patients with sudden deafness as compared to the healthy population (61; 66) as well as in those with other forms of autoimmune inner ear disease (95). IgE levels were elevated in patients with acute-onset low-tone sensorineural hearing loss, were associated with increased allergic response, and predicted relapse as well as progression to Meniere disease (64). Human leukocyte antigen phenotyping has not been extensively evaluated, but available studies have produced variable results without a strong association identified (89).

Autoimmune mice treated with prednisolone or aldosterone were protected from strial damage (111).

Epidemiology

Autoimmune sensorineural hearing loss is a rare clinical disorder. The estimated yearly incidence is less than five cases per 100,000, and its prevalence is 15 out of 100,000. Some authors report that this condition accounts for less than 1% of all cases of hearing loss, even though the diagnosis of autoimmune sensorineural hearing loss might be overlooked without a specific diagnostic test (11). An approximate 2-to-1 female predominance is reported. Although age at presentation varies from childhood to old age, in most patients, symptoms occur in the third to sixth decades, with a peak incidence in the fifth decade (77). An association with other autoimmune disorders is reported in 30% of presenting patients (47; 20). The prevalence of hearing loss in various autoimmune diseases was reviewed nicely in one study (67). The risk of sudden sensorineural hearing loss was examined in a Korean population with established autoimmune diseases, and the results showed 1.1% of an autoimmune disease group experienced sensorineural hearing loss compared to 0.7% of a matched control group (50). Hearing loss prevalence was significantly higher in patients with antiphospholipid syndrome, multiple sclerosis, rheumatoid arthritis, Sjogren syndrome, and Behcet disease.

Prevention

No known methods of disease prevention for autoimmune sensorineural hearing loss exist; however, protection of remaining hearing from other forms of hearing loss is recommended. These recommendations include avoidance of scuba diving and exercising good noise protection of the good ear.

Differential diagnosis

Confusing conditions

Autoimmune sensorineural hearing loss is a unique clinical entity with a characteristic history and a response to immunotherapy. Other forms of sensorineural hearing loss may share features with autoimmune sensorineural hearing loss but can usually be differentiated by history or clinical response.

In patients with hearing loss, history taking is a very important step in trying to determine the etiology: it is important to establish the length of time over which the hearing loss has developed, associated symptoms (tinnitus, vertigo, pain, ear discharge), and predisposing factors (eg, noise exposure, chemotherapy, antibiotic treatments, prior ear surgery, trauma, meningitis, or family history of hearing loss) (77). A complete review of systems should be performed in all patients because up to 30% of patients have or will develop a systemic autoimmune disease.

Among the other forms of sensorineural hearing loss that may be confused with autoimmune sensorineural hearing loss are sudden deafness, Meniere disease, cochlear otosclerosis, syphilitic deafness, Cogan syndrome, noise-induced hearing loss, ototoxic hearing loss, and acoustic tumors.

In addition to autoimmune sensorineural hearing loss, the differential diagnosis of rapidly progressive hearing loss includes the following: intracranial etiologies (eg, meningioma, lymphoma, metastatic deposit, cavernous angioma, meningitis, superficial siderosis), paraneoplastic syndromes (eg, small cell lung carcinoma, thymoma), autoimmune syndromes, infective disorders (eg, syphilis, human immunodeficiency virus), and medication-induced causes (60).

Sudden deafness or sudden sensorineural hearing loss differs from autoimmune hearing loss in that it characteristically develops over a matter of hours (within 72 hours or less), occurs unilaterally, and is often accompanied by tinnitus.

Autoimmune sensorineural hearing loss typically is somewhat insidious in onset, progressing over weeks to months, but more rapid than the development of presbycusis. The course is typically fluctuating and affects bilateral hearing, although the audiometric threshold may be asymmetric. From 25% to 50% of patients also have tinnitus and aural fullness. Facial palsy, as well as destruction of the tympanic membrane, middle ear, and mastoid may occur, but physical examination is usually normal.

Vasculitic processes tend to present as having a small conductive component due to otitis media, with serous otitis media being the most common type (129). Vestibular symptoms, such as imbalance, ataxia, motion intolerance, and positional or episodic vertigo, may be present in up to 50% patients. These patients can have an antecedent viral infection, but often the etiology cannot be determined (83). Despite a different disease time course, evidence supports an immunologic basis for sudden deafness in at least some cases (08).

Meniere disease is characterized by sudden, fluctuating hearing loss, episodic vertigo, tinnitus, and aural fullness; it is usually unilateral, especially early in the course. Meniere disease usually responds to dietary adjustments and diuretics and often will have characteristic findings on electrocochleography. Despite these distinctions, some authors have suggested that some patients with severe Meniere disease, particularly those not responding to conventional therapy, may have an autoimmune etiology (125).

Hearing loss from cochlear otosclerosis typically has a positive family history, flat audiogram, and slow progression over years. It can be differentiated from the more rapidly progressing autoimmune sensorineural hearing loss, as this type usually lacks a hereditary component and improves with glucocorticoids.

Syphilitic deafness is distinguished by significant vertigo and hearing loss that progresses over months to years, with a positive CSF fluorescent treponema absorption antibody (FTA-ABS) assay.

Cogan syndrome is a distinct systemic disorder characterized by audiovestibular dysfunction in the form of acute sensorineural hearing loss and vestibular imbalance or ataxia combined with nonsyphilitic interstitial keratitis (74; 23). The cause is likely a postinfectious immune response, and glucocorticoids are of benefit if initiated promptly (74).

Susac syndrome is a vasculopathic condition that may affect vision (secondary to retinal artery occlusion), the brain, and hearing (22; 49; 06; 09; 96; 105; 106). The auditory component of this triad may precede the other two manifestations (22). Autoimmune-mediated occlusions of the microvasculature in the brain, retina, and inner ear lead to CNS dysfunction, hearing deficits, and branch retinal artery occlusion (49).

Muckle-Wells syndrome is an autoinflammatory disease, part of the spectrum of a rare hereditary inflammatory disorder: cryopyrin-associated periodic syndrome (CAPS). In Muckle-Wells syndrome, sensorineural hearing loss starts in adolescence, and high-frequency sensorineural hearing loss is universal. Associated clinical features are skin rashes, fever, conjunctivitis, arthralgias, abdominal pain, and amyloidosis (57).

NOMID/CINCA is a dramatic autoinflammatory condition manifesting with fever, meningitis, severe joint damage, sensorineural hearing loss, vision loss, uveitis, papilledema, and sensorineural hearing loss that starts in infancy or young childhood (31).

Noise-induced sensorineural hearing loss should readily be distinguished from autoimmune sensorineural hearing loss by antecedent noise exposure.

Toxic sensorineural hearing loss can present as progressive or sudden sensorineural hearing loss. These cases are recognized by a prior history of exposure to known ototoxic agents, including aminoglycosides and chemotherapeutic agents.

Acoustic tumors present with asymmetric sensorineural hearing loss over months to years and have diagnostic radiographic findings absent in autoimmune hearing loss.

Sensorineural hearing loss may be the presenting symptom of paraneoplastic syndrome (34). The hearing loss is usually followed by involvement of different areas of the nervous system. Paraneoplastic sensorineural hearing loss has been described in patients with Hu antibodies, small cell lung cancer (94), sensory neuronopathy, kelch-like protein 11 (KLHL11) antibodies, brainstem encephalitis, and testicular seminomas (36). The cause of the hearing loss is unclear, but in patients with Hu antibodies and sensory neuronopathy, the reason is the loss of cochlear neurons (94).

Other differential diagnoses of autoimmune hearing loss include enlarged vestibular aqueduct syndrome, and Charcot-Marie-Tooth disease (17).

Diagnostic workup

Autoimmune hearing loss is usually diagnosed by history and physical examination to include neuro-otologic evaluation and audiometry. Improved hearing thresholds after immunosuppressive treatment are a confirmatory feature of the diagnosis. No single diagnostic examination or laboratory study can definitively identify this disorder, nor is a “response” to immunotherapy a definitive diagnostic test.

In obtaining a history, emphasis must be placed on the temporal aspects of the hearing loss and any possible antecedent event, such as viral illness, trauma, or aminoglycoside use. Autoimmune disease can also result in conductive hearing loss and visual loss.

Careful evaluation for vision changes is important as several autoimmune disorders associated with autoimmune sensorineural hearing loss also commonly involve the eye, including Susac syndrome, Cogan syndrome, HLA-B27 sclero-uveitis, and Vogt-Koyanagi-Harada syndrome.

At a minimum, evaluation should include an assessment of pupillary reactions (including swinging light test for an afferent pupillary defect), visual acuity, visual fields, and fundoscopy.

Careful evaluation for signs and symptoms of a systemic autoimmune disorder that may predispose to immune-mediated hearing loss is important. In 15% to 30% of cases, patients with autoimmune hearing loss have or will develop a systemic autoimmune disease (77).

Differentiation between autoimmune hearing loss and sudden hearing loss is important. Generally, autoimmune hearing loss develops over weeks to months and involves both ears. Sudden hearing loss is usually unilateral and develops within 72 hours.

Ruling out the diagnosis of Cogan syndrome is important, not only because hearing is often lost and vision can be lost, but also because 10% of cases are complicated by aortic insufficiency, which can be life-threatening (28). Firm diagnostic criteria have not been established, and there are no tests that prove or disprove the diagnosis. Diagnosis is made on clinical grounds following the exclusion of other conditions with similar presentations.

If the hearing loss is acute and bilateral, psychiatric, neurologic, and hematologic causes should be considered. Reported etiologies of acute hearing loss have included psychogenic (typically presenting with inconsistencies and variabilities on testing and a discrepancy between pure tone audiometry and auditory brainstem response) (05) and hearing loss related to tumor spread, particularly due to diffuse metastatic leptomeningeal carcinomatosis (56). Sudden hearing loss may also follow shortly after neurosurgical procedures such as intracranial surgery and lumbar punctures; such episodes are typically limited and resolve spontaneously. Neurologic causes can include diffuse encephalitis or paraneoplastic syndromes. Sudden hearing loss may also be a manifestation of vascular insufficiency to the brain – either in the form of acute vertebrobasilar insufficiency due to blood flow occlusion (101) or secondary to decreased cardiac output, as has been described with mitral stenosis (35). A subset of patients who experience an episode of sudden sensorineural hearing loss have 1.64 times greater risk of stroke than controls over a 5-year period (63). Given these findings, consideration for a thorough cardiac and neurologic workup should be made as well as close follow-up for patients judged most at risk.

Following a thorough history and physical examination, including otoscopy and tuning fork tests, pure tone audiometry and word recognition testing is required to determine the type and degree of hearing loss. Autoimmune sensorineural hearing loss is most often bilateral and asymmetrical (73). The audiogram further serves as a baseline study to document any progression of hearing loss or response to treatment. Electronystagmography can also evaluate vestibular function (47).

Neuroimaging with gadolinium-enhanced MRI should be obtained if the cause of hearing loss is not identified with otoscopy and audiometry.

If the patient cannot undergo MRI, alternatives include CT, auditory brainstem response evaluation, or both, although these are less sensitive than MRI for detection of retrocochlear abnormalities (93). High-resolution, gadolinium-enhanced, T1-weighted MRI studies have shown enhancement of the vestibule, semicircular canals, vestibular nerve, and cochlea in patients with Cogan syndrome and acute disease, whereas patients with chronic deficits but no acute disease have narrowing or occlusion of semicircular canals on images obtained by the 3-dimensional constructive interference in steady-state technique (13; 26). PET may be a useful technique for assessing disease activity in patients with autoimmune inner ear disease (71). Cerebral angiographic findings of vasculitis, including alternating segments of stenosis and ectasia in intracranial arteries as well as a small aneurysm at the vertebrobasilar junction, have been described (02). Autoimmune hearing loss should be suspected when no clear etiology is noted on imaging studies and symptoms are progressing too slowly to be sudden sensorineural hearing loss and too fast to be presbycusis (77).

Excessive blood testing is expensive and often of no clinical consequence (46). Nevertheless, it may be reasonable to obtain serum tests that might confirm the suspicion of a systemic autoimmune disease, such as circulating immune complexes, quantitative immunoglobulin levels, antinuclear antibodies, and antibodies to extractable nuclear antigens, rheumatoid factor, complement levels, sedimentation rate, cryoglobulins, ANCA (anti-neutrophil cytoplasmic antibody), and thyroid autoantibodies. Negative serologic and treponemal tests for syphilis are mandatory to rule out congenital and acquired syphilis, which are the conditions most similar to Cogan syndrome. Sarcoidosis is the next most likely diagnosis to be excluded in patients with Cogan syndrome. Pathologic findings of necrotizing vasculitis have been demonstrated by biopsy of the skin, kidney, liver, spleen, gastrointestinal tract, subcutaneous nodules, muscle, myocardium, and coronary arteries (117). Bone marrow and brain biopsy generally have nonspecific findings (117).

Heat shock protein 70 (Hsp-70) antibodies have been examined as a diagnostic test for autoimmune hearing loss, but the evidence supporting this test’s diagnostic utility is weak (48) because it has a sensitivity of only approximately 50% (77). HSP70 antibodies have subsequently been detected in controls at a rate similar to cases (114). Anti-CTL-2 antibodies are found in 50% of patients with autoimmune sensorineural hearing loss; however, antibody testing is not commercially available, and the diagnostic value has yet to be evaluated (77). Of note, in humans with immune-mediated hearing loss, elevated TNF levels have been associated with a greater response to treatment with steroids (114).

Although a positive laboratory test result may suggest an autoimmune process, it is important that these tests not be overinterpreted, and simple positivity should not be viewed as diagnostic of an autoimmune process. Clinical experience suggests more specific immune complex assays are unlikely to aid in the diagnosis of autoimmune sensorineural hearing loss if the erythrocyte sedimentation rate is normal (107). Normal results, however, certainly do not exclude an immune-mediated etiology for hearing loss.

A diagnostic tool that is fairly specific for autoimmune sensorineural hearing loss is the response to treatment. Patients with the disorder have hearing levels that improve with treatment and deteriorate with interruptions in treatment, only to again have hearing improvement with reinstitution of therapy. This response to treatment is the hallmark of autoimmune sensorineural hearing loss and its most consistent diagnostic test.

Management

A multidisciplinary approach is recommended with otolaryngology, rheumatology, and audiology involvement. Rheumatologic consultation is recommended, especially if the need to resort to immunosuppressive agents beyond corticosteroids is considered.

Classically, autoimmune sensorineural hearing loss improves with initiation of immunotherapy, deteriorates with discontinuation of therapy, and recovers with reinstitution of treatment.

Advances in treatment remain complicated by the lack of reliable and easily available diagnostic testing as well as the lack of an animal model.

Oral glucocorticoids. High-dose glucocorticoids block the immune response or reduce inflammation and are considered first-line therapy. Contraindications to using steroids may include active infection, peptic ulcer disease, uncontrolled diabetes mellitus, glaucoma, or uncontrolled hypertension (83; 42). Dose and duration recommendations for therapy vary. Steroid doses tapered too rapidly can result in deterioration of hearing (53). The current standard of care includes a trial of oral prednisone at an initial dose of 60 mg/kg/day or 1 mg/kg per day for 4 weeks (93). Hearing tests are performed at therapy onset and after 1 month of treatment. Therapy is continued in those patients until monthly audiograms demonstrate stabilization (77). Steroids are tapered over 8 weeks to a maintenance dose of 10 mg for a total treatment time of at least 6 months. Steroid doses tapered too rapidly can result in deterioration of hearing (53). In patients who fail the initial 4-week trial, steroids are tapered over 12 days.

Oral glucocorticoids are also useful for the prevention of hearing loss when used early in the course of Cogan syndrome, before substantial loss has occurred, as well as for treating the vasculitic manifestations of Cogan syndrome; in a series, 22% of patients treated with glucocorticoids died, compared to 67% of untreated patients (117). Immunomodulatory agents have been successfully used in glucocorticoid-unresponsive or -dependent patients to improve hearing, control vasculitis, and reduce relapses (102). Hearing fluctuations that occur late in the course of the disease respond to oral thiazide diuretics (44; 45). Aortic valve replacement can be lifesaving in patients with Cogan syndrome who have symptomatic aortitis and aortic insufficiency. Coronary artery bypass grafting has been used successfully in patients with coronary arteritis (117).

Intratympanic steroid administration. Human studies of intratympanic steroid administration for autoimmune sensorineural hearing loss have been limited to small uncontrolled case series (103; 87; 27; 77), and there has not been a good randomized controlled trial. Overall, it remains to be shown whether oral or intratympanic steroids are more efficacious or whether other distinct advantages exist for intratympanic steroid administration in autoimmune inner ear disease (114).

Immunosuppressive agents. Immunomodulatory agents, such as methotrexate, cyclophosphamide, azathioprine, or mycophenolate mofetil, may be used to supplant the glucocorticoids if the patient has had a positive response, although there are no high-quality studies supporting these agents. A retrospective analysis suggested that there remains a subset of patients with autoimmune hearing loss who are steroid nonresponders but show improvement with other cytotoxic medications (59). Although methotrexate showed promise in preliminary studies, in a randomized, double-blind, placebo-controlled study, it failed to show efficacy in preserving hearing recovery gained through prednisone therapy (43). A prospective open-label study of 17 patients with autoimmune hearing loss (five of whom had idiopathic autoimmune hearing loss) demonstrated audiometric improvement in 65% (11 of 17) at 12 months (70). Other reports have included azathioprine or mycophenolate mofetil as monotherapy or combined with prednisone (98), but controlled studies have yet to be conducted. A review of one group’s 10-year experience with various nonbiological steroid-sparing agents in 16 patients with autoimmune hearing loss suggested a beneficial modest response (12). Given the relative paucity of data regarding this situation, use of these agents as first-line therapy cannot be recommended.

Monoclonal antibodies. A systematic review identified 12 studies investigating the impact of biological medications on hearing outcomes, including one randomized control trial, seven prospective cohort studies, and four retrospective cohort studies (04). Seven biological medications (ie, etanercept, infliximab, adalimumab, golimumab, rituximab, anakinra, and canakinumab) were identified for three unique molecular targets: TNF-alpha, CD20, and IL-1. The effects of biological medications in treating sensorineural hearing loss were highly variable without clear efficacy of any of these drugs, likely due in part to the rarity and multiple disease associations of autoimmune sensorineural hearing loss and also to the low quality of available studies (90; 69; 115; 77; 113; 114). Several medications seemed to alleviate symptoms associated with autoimmune sensorineural hearing loss, such as vertigo and tinnitus, but available data were not generally derived from controlled trials. Although biological medications may be promising therapeutics in autoimmune sensorineural hearing loss, the evidence for their utility is inconclusive. Large-scale randomized control trials are required to establish the efficacy of biological medications in treating hearing loss.

A 12-week blinded, placebo-controlled, randomized clinical trial of etanercept performed on 20 patients with autoimmune hearing loss revealed no statistically significant effect versus placebo (18).

Presently, there is insufficient evidence that any of the proposed alternative treatments can replace steroids as initial treatment. More studies are needed to test the value of biological therapies and how to manage steroid-resistant disease (97).

Auditory amplification. In those patients whose hearing loss is stabilized with therapy but does not return to premorbid levels, amplification devices are often employed.

Cochlear implants. When bilateral inner-ear disease leaves patients with severe or profound sensorineural hearing loss, cochlear implants successfully restore functional hearing (30). Although cochlear implant outcomes are generally excellent, the utility of cochlear implants may be adversely affected by intracochlear fibrosis intraoperatively, and the likelihood of implant performance fluctuation is related to ongoing inflammation in the cochlea (30).

Enoxaparin. Enoxaparin, a low-molecular-weight heparin, has shown promise in managing immune-related sensorineural hearing loss. Patients receiving enoxaparin twice daily demonstrated both a subjective and objective reduction in symptoms with no reported side effects (78).

Hyperbaric oxygen therapy. Hyperbaric oxygen therapy increases oxygen supply to ischemic cochlear structures in sensorineural hearing loss. The American Academy of Otolaryngology-Head and Neck Surgery recommends hyperbaric oxygen therapy as an optional therapy to be used within 3 months of sensorineural hearing loss onset. A meta-analysis including three randomized controlled trials and 16 nonrandomized studies, pooling 2401 patients, revealed that compared to medical therapy alone, hyperbaric oxygen therapy combined with medical therapy may be more efficacious for patients treated in a salvage setting, with severe-to-profound (greater than 70 dB HL) sensorineural hearing loss, and treated for a total treatment duration of 1200 minutes (104).

Follow-up. Patients who have successfully been managed and no longer have active symptoms should be followed closely. It is commonly advised to repeat audiometric testing over the course of a year (at 2 months, 6 months, and 12 months after the onset of hearing loss) to document recovery, guide aural rehabilitation (and hearing aid fitting and adjustment), and monitor for signs of relapse in the affected ear or development of hearing loss in the contralateral ear, which would warrant consideration of other diseases, such as Meniere disease.

Outcomes

Prognosis for patients who do not receive therapy is poorly categorized; the anticipated outcome is progressive hearing loss and, ultimately, sensorineural deafness. The prognosis for those patients with autoimmune hearing loss who receive and respond to therapy is usually good, with recovery of most, if not all, premorbid hearing. Patients with systemic manifestations of autoimmune disease at presentation generally have a lower response rate and those with isolated vestibular symptoms are usually responsive to steroids (20). The long-term outcomes in these patients are variable, with some patients requiring continued immunotherapy for several years to prevent relapses whereas others can complete treatment in a period of months (73; 47; 83; 42). The response rates to treatment are difficult to determine and the use of response to treatment as a diagnostic criterion artificially elevates the success of therapy. The consensus opinion is that spontaneous recovery almost always occurs within 2 weeks. Given that steroids have been reported to work best within 1 to 2 weeks of symptom onset with little benefit seen in cases over 4 weeks, there is a sense of urgency in making an appropriate diagnosis and instituting therapy to maximize successful outcomes.

Special considerations

Pregnancy

Three cases of pregnancy associated with Cogan syndrome have been reported, with none reporting obstetric or postpartum complications (21; 19; 109). No information is available regarding the effects of pregnancy on autoimmune hearing loss. However, great caution should be maintained in treating this disorder during pregnancy. The cytotoxic agents should not be used in pregnancy. Although prednisone is not contraindicated, a careful risk-versus-benefits approach should be taken with its use during pregnancy.