Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Autoimmune hearing loss is a potentially reversible form of hearing loss defined by rapidly progressive sensorineural loss and a characteristic recovery with immunosuppressive therapy. The pathogenesis of the disorder is uncertain, but damage to inner-ear structures is thought to occur through an immune-mediated process. In this article, the authors review the current understanding of the disorder. Cogan syndrome is included as well. The authors also provide an update on treatments for autoimmune hearing loss.
• Autoimmune sensorineural hearing loss is a well-described clinical entity that has a not fully understood pathogenesis.
• Cogan syndrome is characterized by audiovestibular and ocular disease (interstitial keratitis).
• Progress has been made in understanding the underlying pathophysiology, both in animal models and human patients.
• Treatment remains aimed at controlling a likely abnormal immune response to inner-ear antigens, and study data are reviewed in this article regarding specific agents and therapeutic management approaches.
• Classically, autoimmune sensorineural hearing loss improves with initiation of treatment, deteriorates with discontinuation of therapy, and recovers with reinstitution of treatment.
Autoimmune sensorineural hearing loss is a well-described clinical entity with an uncertain pathogenesis. Known also as "immune-mediated sensorineural hearing loss," "autoimmune inner-ear disease," and "steroid-responsive sensorineural hearing loss," this disorder is one of only a few forms of sensorineural hearing loss that can be treated.
A relationship between autoimmune diseases and hearing loss is well recognized, with descriptions of sensorineural loss seen in such systemic autoimmune diseases as systemic lupus erythematosus (SLE), polyarteritis nodosa (PAN), granulomatous polyangiitis (GPA) (former nomenclature – Wegener granulomatosis), and rheumatoid arthritis (35). In addition, reports have also described associations with celiac disease (100), primary antiphospholipid syndrome (11; 102), Behcet disease (22), Sweet syndrome (13), ankylosing spondylitis (01), systemic sclerosis (56), sclerouveitis in the setting of HLA-B27 positivity (78), and Cogan syndrome (66). See Table 1 in the “Etiology” section for a complete listing of associated diseases.
An immune response directed against the inner ear resulting in hearing loss was first described in 1979 (62). McCabe described sensorineural hearing loss in 18 patients with a variable presentation of progressive bilateral asymmetrical sensorineural hearing loss accompanied by vestibular symptoms. These patients showed negative serologic testing, with the notable exception of a positive response to inner-ear antigens. Treatment with dexamethasone and cyclophosphamide substantially improved hearing. The distinctive clinical course, laboratory findings, and clinical response to immune therapy raised the specter of this entity to being autoimmune mediated. Subsequent literature described a characteristic clinical presentation to include rapid onset (usually unilateral), as well as a more slowly progressing form of sensorineural hearing loss (63).
A condition referred to as "steroid-responsive bilateral sensorineural hearing loss" appeared in the literature in the 1980s (48). Several patients diagnosed with idiopathic sensorineural hearing loss showed improvement in audiologic measurements following steroid therapy and subsequent deterioration of auditory sensitivity on discontinuation of treatment. These patients also revealed elevated serum levels of immune complexes that responded to steroid treatment (47). Earlier was described an immune complex-mediated disorder with features of vasculitis that targeted the inner ear and improved with glucocorticoids (98).
Although rigid diagnostic criteria for autoimmune sensorineural hearing loss are currently not defined, the hallmark features of progressive sensorineural hearing loss and steroid responsiveness are widely recognized features.
• Autoimmune hearing loss is believed to constitute less than 1% of all cases of acute/subacute sensorineural hearing loss.
• Hearing loss is usually bilateral (greater than 80% of patients).
Autoimmune 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 within hours up to 3 days) to a chronic progressive form (developing more slowly over several months). The typical time frame is usually between these 2 extremes, presenting as a rapidly progressive and often fluctuating bilateral sensorineural hearing loss (08), evolving over weeks to months. This usually involves high frequencies and is most often represented by down-sloping audiogram. A low-frequency loss is also possible, although less common. Although it is bilateral in up to 80% of cases, unilateral presentations also occur (42). The presence of other immune diseases is also common, with as many as 30% of patients exhibiting some form of systemic immune-related disease (42). Autoimmune hearing loss can be precipitated by treatment with immune checkpoint inhibitors, which activates the immune system to fight the underlying cancer and associates with an increased frequency of autoimmune disorders (77).
In addition to complaints of hearing loss, nearly half of autoimmune sensorineural hearing loss patients report other vestibuloauditory symptoms including aural fullness, tinnitus, lightheadedness, and vertigo (42). Facial nerve palsy is also observed occasionally (62). 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 (42). The incidence of autoimmune hearing loss is believed to constitute less than 1% of all cases of hearing impairment with dizziness.
Cogan syndrome is characterized by the mix of audiovestibular symptoms and inflammatory ocular disease, occurring concomitantly or within 6 months of each other. This is usually a relapsing condition (26). There can be multisystem involvement (49). 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 (26). The audiovestibular dysfunction leads to progressive hearing loss and deafness in 60% of patients (39).
An otherwise healthy 28-year-old, African-American male presented with a complaint of hearing loss in his right ear for several weeks’ duration. He had mild dysequilibrium but no vertigo or tinnitus. Physical examination was normal. Audiometric analysis revealed an asymmetric, moderate to severe sensorineural hearing loss in the right ear with a discrimination score of 72%. Blood chemistry, including syphilis assay, was normal and MRI with gadolinium revealed no cerebellar pontine angle lesion. 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 dysequilibrium. Audiogram revealed the persistence of the right-sided hearing loss and the development of moderate (40 dB) sensorineural loss in the left ear. Discrimination was 80% in the left ear. Electrocochleography and electronystagmography were normal. He was started immediately on a 4-week course of prednisone at 60 mg/day. Follow-up audiogram at 4 weeks showed improvement in both 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.
Direct tumor invasion
The exact etiology of autoimmune hearing loss is unknown; however, available evidence suggests that an autoimmune response is directed against inner-ear tissues. Controversy exists as to whether the inner ear is targeted directly through a cell-mediated immune response or whether the damage is the result of a humoral immune complex destruction of key inner-ear structures. Viral, vascular, and immunologic mechanisms have all received consideration (29).
Advances in immunology and molecular biology 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 a source of controversy.
The inner ear, once thought to be an immunologically privileged site, is much more responsive to immune stimulation than the brain and acts as an afferent limb of the immune pathway (33). Both humoral and cell-mediated responses are established for inner-ear tissues and fluids and help to protect these vital structures from infection (37). This immune response and resultant inflammation, however, can result in serious injury to the delicate cochlear 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 (91).
Direct evidence of immune-mediated damage to inner-ear structures, however, is not easily demonstrated. The first successful induction of autoimmune sensorineural hearing loss in an experimental model was by Yoo and colleagues (110). They successfully produced hearing loss and vestibular disease in rats by immunizing with type II collagen, an extracellular matrix protein found throughout the inner ear. Histological analysis of inner ears from these animals demonstrated significant perivascular inflammation and immune complex deposition compared with control animals. In similar experiments with the guinea pig model, Yoo and colleagues found injury to the stria vascularis, organ of Corti, and spiral ganglion cells (106). These findings suggest the existence of similar mechanisms in humans. Subsequent clinical studies used type II collagen as the antigen for lymphocyte transformation tests and found positive responses in 34 of 68 patients with progressive sensorineural hearing loss compared to only 4 of 68 controls (05). 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) were detected in 13 of 21 blots (46). Animal models have been developed utilizing type II (107) and type IX collagen (12) as well as the myelin protein P0 protein (58) and tubulin (108). These results support the role of a collagen-mediated pathogenesis of autoimmune sensorineural hearing loss. Other authors, however, obtained conflicting results, suggesting that at least 1 other, and perhaps several other, antigens are targets for the immune response (37). Investigators previously reported on a 68-kDa antigen, which was thought to represent heat shock protein 70 (HSP70), identified in serum of patients with progressive hearing loss suspected to be immune-related (07). However, the identity of this antigen has been called into question in several subsequent studies (105; 70). Nair and colleagues, who had previously developed monoclonal antibodies to cells isolated from guinea pig organs of Corti, observed that mice carrying the Kresge Hearing Research Institute-3 (KHRI-3) antibody developed hearing loss (71). After isolating and purifying the inner-ear antigen, their group was able to sequence it and identify multiple peptide sequence identical to those in human choline transporter-like protein 2 (CTL2). Choline is thought to play 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.
In addition to controversy surrounding the antigenic stimulus for immune-mediated hearing loss, there is debate concerning 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 (32). Once the inner ear has become activated by a number of potential processes, new cells either form or enter from the systemic circulation, penetrating the blood labyrinthine barrier. Several authors have demonstrated the presence of macrophages, B cells, and T cells in the perisaccular space in both humans and animals (32; 03). It is thought that 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 post-stimulation, immune cells begin to accumulate around the blood vessels within the spiral modiolar vein and then begin to enter the scala tympani (34). Control of this process is not well understood. Tomiyama and Harris have previously demonstrated that ablation of the endolymphatic sac reduces immune responses in the cochlea (Tomiyama and 33). This process leads to production of IL-2, which is normally absent from the perilymph in the resting state, peaking at approximately 18 hours after stimulation and declining 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 reduce. IgG, IgA, and IgM immunoglobulin presence in the perilymph has been demonstrated in humans as well as animals, but its origin remains to be elucidated (104). 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 (52; 65; 103; 72; 54). 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. The importance of TNF-alpha was established in the KLH model of autoimmune inner-ear disease when Satoh and colleagues showed that this was the first cytokine expressed by inner-ear-infiltrating cells following systemic KLH-antigen immunization and infusion into the cochlea (83). Investigators also showed that the use of etanercept – a TNF-alpha antagonist – reduced cell infiltration and cochlear fibrosis compared to controls (75). Similar results were obtained with intraperitoneal etanercept injection in the same model (101). Finally, it was elucidated that the 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 (84). From this, it is easy to see how continuous antigen exposure can lead to a chronic inflammatory cascade that results in damage to the sensitive structure of the inner ear.
An association exists as well with antiphospholipid antibodies, mainly anti-cardiolipin and anti-beta-2-glycoprotein-1 (69). 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 autoimmune hearing loss is unclear.
Trune and colleagues showed that in experiments autoimmune mice treated with prednisolone or aldosterone were protected from strial damage (94). Currently, there are no human histopathologic findings available to validate these experimental models.
A very thorough review of our understanding of the pathogenesis of autoimmune inner ear disease has been published (28).
Autoimmune hearing loss is a rare clinical disorder with an unknown incidence and prevalence. The estimated yearly incidence is less than 5 cases per 100,000, and its prevalence is 15 out of 100,000. In the United States, the prevalence is estimated to be 45,000 patients per year (96). Some authors report that this condition accounts for less than 1% of all cases of hearing loss, even though the diagnosis of autoimmune hearing loss might be overlooked in the absence of a specific diagnostic test (08). 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 (67), with a peak incidence in the fifth decade. An association with other autoimmune disorders is reported in 30% of presenting patients (42; 18). The prevalence of hearing loss in various autoimmune diseases was reviewed nicely in 1 study (57). Sudden sensorineural hearing loss was examined in a Korean population with established autoimmune diseases, and the results showed 1.09% of an autoimmune disease group experienced sensorineural hearing loss compared to 0.73% of a matched control group. Hearing loss was significantly higher in patients with antiphospholipid syndrome, multiple sclerosis, rheumatoid arthritis, Sjogren syndrome, and Behcet disease (45).
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.
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 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 figure out potential etiology: it is important to establish the length of time over which the hearing loss has developed, associated ontological symptoms (tinnitus, vertigo, pain, ear discharge), and predisposing factors (such as noise exposure, chemotherapy, antibiotic treatments, prior ear surgery, trauma, meningitis, or family history of hearing loss) (67). 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.
Sudden deafness or sudden sensorineural hearing loss differs from autoimmune hearing loss in that it characteristically occurs instantly or over a matter of hours (within 72 hours or less), occurs unilaterally, and is often accompanied by tinnitus.
Autoimmune hearing loss generally is more insidious in onset than acute hearing loss, progressing over weeks to months, but more rapid than presbycusis. The course is typically fluctuating and affects bilateral hearing, although the audiometric threshold may be asymmetric. Almost 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 (111). 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 (73). Despite a different disease time course there is evidence to support an immunologic basis for sudden deafness in at least some cases (06).
Meniere disease is characterized by sudden, fluctuating hearing loss, episodic vertigo, tinnitus, and aural fullness and is unilateral in most cases. Meniere disease usually responds to dietary adjustments and diuretics and often will have characteristic findings on electrocochleography. Despite these distinctions, authors have suggested that some patients with severe Meniere disease, particularly those not responding to conventional therapy, may have an autoimmune etiology (106).
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 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 cerebrospinal fluid fluorescent treponema absorption antibody assay.
Cogan syndrome is a distinct systemic disorder characterized by vestibuloauditory dysfunction in the form of acute sensorineural hearing loss and imbalance combined with the ocular finding of nonsyphilitic interstitial keratitis. The cause is likely a postinfectious immune response, and glucocorticoids are of benefit if initiated promptly (64). The distinction between Cogan syndrome and autoimmune hearing loss is made based predominantly on ocular findings (21).
Susac syndrome is a vasculopathic condition that may affect vision (secondary to retinal artery occlusion), the brain, and hearing. It is possible that the hearing component of this triad may precede the other 2 manifestations (20). Autoimmune-mediated occlusions of the microvasculature in the brain, retina, and inner ear lead to CNS dysfunction, hearing deficits, and branch retinal artery occlusion (44).
In Muckle-Wells disease hearing loss starts in adolescence, and high frequency hearing loss is present in 100% of patients; associated clinical features are skin rashes, fever, conjunctivitis, and amyloidosis (51).
NOMID/CINCA is a dramatic autoinflammatory condition manifesting with fever, meningitis, severe joint damage, hearing loss, vision loss, uveitis, papilledema, and sensorineural hearing loss that starts in infancy or young childhood (27).
Noise induced hearing loss should readily be distinguished from autoimmune loss by antecedent noise exposure.
Toxic deafness can present as progressive sensorineural hearing loss, but may also present as sudden hearing loss. These cases are recognized by a prior history of exposure to known ototoxic agents including aminoglycosides and chemotherapeutics.
Acoustic tumors present with asymmetric 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 a paraneoplastic syndrome (30). The hearing loss is usually followed by involvement of different areas of the nervous system. 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 (80).
Other differential diagnoses of autoimmune hearing loss are represented by enlarged vestibular aqueduct syndrome, endocrine hypertension, and Charcot-Marie-Tooth disease (14).
• There is no single diagnostic examination or laboratory study that definitively confirms the diagnosis of autoimmune sensorineural hearing loss.
• MRI studies are indicated to rule out structural lesions.
• Extensive blood testing is not indicated unless other features suggesting an autoimmune disorder are present.
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. There is no single diagnostic examination or laboratory study that definitively identifies this disorder, nor is a “response” to immunotherapy a definitive diagnostic test.
In obtaining a history, emphasis needs to be placed on the temporal aspects of the hearing loss and any possible antecedent event such as viral illness, trauma, or aminoglycoside use. Careful evaluation for signs and symptoms of a systemic autoimmune disorder that may predispose to an 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 (67). Autoimmune disease can also result in conductive hearing loss. As such, 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 will develop in 72 hours or less. With regard to autoimmune etiologies, 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 (25). 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 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 a discrepancy between pure tone audiometry and auditory brainstem response) (04) and hearing loss related to tumor spread, particularly due to diffuse metastatic leptomeningeal carcinomatosis (50). 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 (85) or secondary to decreased cardiac output, as has been described with mitral stenosis (31). Interestingly, it has been reported that 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 (55). 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 exam including otoscopy and tuning fork tests, an audiologic evaluation with air- and bone-conduction thresholds as well as speech discrimination scores is required to determine the type and degree of hearing loss. Autoimmune sensorineural hearing loss is most often bilateral and asymmetrical (63). The audiogram further serves as a baseline study to document any progression of hearing loss or response to treatment. Electronystagmography can also be employed to evaluate vestibular function, as it can be abnormal in a number of these patients (42).
If the cause of hearing loss is not identified with otoscopy and audiologic evaluation, then radiographic evaluation with gadolinium-enhanced magnetic resonance imaging to exclude any space-occupying lesion, vascular insufficiency, ischemic disease, or demyelinating disorder in cases of acute symptoms. If the patient is unable to undergo MRI, alternatives include computed tomography scanning, auditory brainstem response evaluation, or both, although these are less sensitive than MRI for detection of retrocochlear abnormalities (79). High-resolution, gadolinium-enhanced, T1-weighted MRI studies have shown enhancement of the vestibule, semicircular canals, vestibular nerve, and cochlea in Cogan syndrome patients with 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-stage technique (10; 23). PET may be a useful technique for assessing activity of disease in patients with autoimmune inner ear disease (61). 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 is 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 (67).
The pathogenesis of sudden sensorineural hearing loss is not well understood; however, it is postulated that a misdirected immune attack on inner ear proteins results in both pro-inflammatory T-cell responses and autoantibody formation. Unlike other autoimmune disease in which a single autoantibody dominates, the presence of autoantibodies in autoimmune inner ear disease is inconsistent with no single diagnostic or prognostic test for therapeutic response (96). Heat shock protein 70 (Hsp-70) antibodies have been examined as a diagnostic test for autoimmune hearing loss. Unfortunately, the evidence supporting this test’s utility for diagnosis is weak (43), with a sensitivity of approximately 50% (67). HSP70 antibodies have subsequently been detected in controls at a rate similar to controls, reducing the utility of HSP antibodies in the diagnosis of autoimmune inner-ear disease (96). Anti CTL-2 antibodies have also been evaluated and are found in 50% of patients with autoimmune hearing loss. However, antibody testing is not commercially available, and the diagnostic value has yet to be evaluated (67). Of note, in humans with immune mediated hearing loss, elevated TNF levels have been associated with greater response to treatment with steroids (96).
A Clinical Practice Guideline for Sudden Hearing Loss promulgated by the American Academy of Otolaryngology – Head and Neck Surgery addressed laboratory testing in the setting of idiopathic sensorineural hearing loss (89). The recommendation that clinicians should not obtain routine laboratory tests was made, but it was acknowledged that specific tests may be useful based on specific individual patient conditions. In the absence of signs and symptoms suggestive of autoimmune disease, the value of including serology testing remains limited (67). With that caveat in mind, it may be reasonable to obtain serum tests that might confirm the suspicion for 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. Excessive blood testing is very expensive and often of no clinical consequence (41). 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 (99). Bone marrow and brain biopsy generally have nonspecific findings (99).
Although a positive laboratory rest 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 hearing loss if the erythrocyte sedimentation rate is normal (90). Normal results, however, certainly do not exclude an immune-mediated etiology for the hearing loss.
A diagnostic tool that is fairly unique to autoimmune 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 hearing loss and its most consistent diagnostic test.
• Steroids are considered first-line therapy.
• The role of intratympanic steroid administration is unclear.
• There is not enough evidence that any of the proposed alternative treatments can replace steroids as initial treatment.
A multidisciplinary approach is recommended with involvement of otolaryngology, rheumatology, and audiologist. 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 treatment, deteriorates with discontinuation of therapy, and recovers with reinstitution of treatment. High-dose glucocorticoids, acting to block the immune response or to reduce inflammation, are considered first-line therapy. Contraindications to use of steroids may include active infection, peptic ulcer disease, uncontrolled diabetes mellitus, glaucoma, or uncontrolled hypertension (73; 37). Dose and duration recommendations for therapy vary. Steroid doses tapered too rapidly can result in deterioration of hearing (48). The current standard of care proposed by Rauch includes a trial of oral prednisone at an initial dose of 60 mg/kg/day or 1 mg/kg per day for 4 weeks (79). Hearing tests are performed at onset of therapy and after 1 month of treatment. Patients’ A response is documented at the end of 4 weeks in 50% to 70% of cases, and therapy is continued in those patients until monthly audiograms demonstrate stabilization (67). 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 (48). In patients who fail the initial 4 week trial, steroids are tapered over 12 days.
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 large studies supporting these agents. A retrospective analysis suggested that there remains a subset of patients with autoimmune hearing loss who are steroid non-responders but show improvement with other cytotoxic medications (53). Methotrexate showed promise in preliminary studies; however, in a randomized, double-blind, placebo-controlled study, it failed to show efficacy in preserving hearing recovery gained through prednisone therapy (38). A prospective open-label study of 17 patients with autoimmune hearing loss (5 of whom had idiopathic autoimmune hearing loss) demonstrated audiometric improvement in 65% (11 out of 17) of patients at 12 months (60). Other reports have included azathioprine or mycophenolate mofetil either as monotherapy or in combination with prednisone (82), but controlled studies have yet to be conducted. A review of 1 group’s 10-year experience with various non-biologic steroid-sparing agents in 16 patients with autoimmune hearing loss indicated a modest response (09). Given the relative paucity of data regarding this situation, use of these agents as first-line therapy cannot be recommended.
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 (99). Immunomodulatory agents have been successfully used in glucocorticoid-unresponsive or -dependent patients to improve hearing, control vasculitis, and reduce relapses (86). Hearing fluctuations that occur late in the course of the disease respond to oral thiazide diuretics (39; 40). In Cogan patients with symptomatic aortitis and aortic insufficiency, aortic valve replacement can be life-saving. Coronary artery bypass grafting has been used successfully in patients with coronary arteritis (99).
Conclusive human studies of corresponding intratympanic steroid administration have been limited, and there has not been a good randomized controlled design. Studies in which patients were offered intratympanic steroid administration, either in place of or as an adjunct to other therapy, seemed to show some efficacy on par with that of oral corticosteroids (87; 74; 24). In a small retrospective case series of 11 patients receiving weekly intratympanic injections of 6-methylprednisolone (12 to 20 mg) for 2 months, 54% of patients had hearing improvement with reduction of vestibular symptoms (67). Overall, it remains to be shown whether oral or intratympanic steroids are more efficacious or whether other distinct advantages exist for use in autoimmune inner ear disease (96). Singh and Irugu carried out a procedure to drill the round window niche for steroid instillation to maximize the drug round window membrane contact area for effective drug diffusion into the inner ear for patients who failed on systemic intravenous and injectable intratympanic steroid therapy (88). Statistically, significant hearing improvement was observed in the patients in whom the intratympanic steroid injection was performed after drilling of the round window niche compared to the control group (88). A study looking into local perfusion of infliximab, a humanized monoclonal antibody to TNF-alpha, in 9 patients divided into 2 groups showed the efficacy of this approach and demonstrated improvement in hearing (97). However, more data are necessary prior to recommending this method as first-line therapy. Additionally, methotrexate used as monotherapy is inferior to use in combination with a TNF inhibitor in RA, and as such MTX and TNFi may hold promise in combination (96).
Despite the above recommendations, a large Cochrane Review noted no evidence of benefit of steroids over placebo, nor was there any difference with addition of antiviral therapy for treatment of sudden sensorineural hearing loss (16).
Studies using etanercept have also been mixed. An early retrospective study and an open-label pilot study showed promising results (76; 59), but 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 (15). Overall, available evidence of anti-TNF agents thus far has failed to show a significant effect on hearing outcomes in patients. Disparity of results may be reflective of changes in timing of treatment relative to corticosteroid use, type of TNF use, and/or the route of administration (96).
Anakinra, an IL-1B inhibitor, was used in a phase I/II open-label, single-arm trial in a small number of patients who were resistant to corticosteroids (95). Seven of ten patients showed an early response, and serum IL-1B plasma levels correlated with response. A study evaluating the pathways that control corticosteroid responsiveness in 47 patients with autoimmune hearing loss revealed that increased IL-1B expression is associated with corticosteroid resistance (67).
Rituximab was tested in an open label pilot study in patients with primary steroid responsive immune mediated hearing loss. A course of Rituxan 1 gram 2 weeks apart prior to starting prednisone tapering was associated with a sustained response following steroid discontinuation in 5 of 7 patients at 24-week follow up.
Presently, there is not enough 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 (81).
Enoxaparin, a low-molecular weight heparin, has shown promise in the management of immune-related sensorineural hearing loss. Patients receiving the enoxaparin twice daily demonstrated both a subjective and objective reduction in symptoms with no reported side effects (68).
In those patients whose hearing loss is stabilized with therapy, but does not return to premorbid levels, amplification devices are often employed. In patients where bilateral inner-ear disease leaves severe or profound sensorineural hearing loss, cochlear implants are successful in restoring functional hearing.
Data on the use of volume expanders, inhaled vasodilators, herbal remedies, and hyperbaric oxygen are very limited. Hyperbaric oxygen therapy (HBOT) is used to increase oxygen supply to ischemic cochlear structures in sensorineural hearing loss. AAO-HNS recommends hyperbaric oxygen therapy as an optional therapy to be used within 3 months of onset of sensorineural hearing loss. A metaanalysis including 3 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) hearing loss, and treated for a total treatment duration of 1200 minutes (88). Oral tolerization therapy has been suggested, similar to the use of ovine myelin basic protein for multiple sclerosis and type II collagen for rheumatoid arthritis, but it has not been attempted due to the still unclear etiologic antigen(s).
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 at 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.
In conclusion, the treatment recommendation for autoimmune sensorineural hearing loss remains high-dose systemic corticosteroids, despite numerous clinical and animal studies. Encouraging early progress has been seen with TNF-alpha antagonists, but more studies are necessary to validate their efficacy and determine the best route of administration. Advances in research and treatment remain complicated by the lack of reliable and easily available diagnostic testing as well as the lack of an animal model.
Prognosis for patients who do not receive therapy is not well 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 (18). 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 (63; 42; 73; 37). 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. 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 in order to maximize successful outcomes.
Three cases of pregnancy associated with Cogan syndrome have been reported, with none reporting obstetric or postpartum complications (19; 17; 92). 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.
Richard M Keating MD
Dr. Keating of Scripps Clinic/Scripps Green Hospital has no relevant financial relationships to disclose.See Profile
Megan Lynch DO
Dr. Lynch of Scripps Clinic/Scripps Green Hospital has no relevant financial relationships to disclose.See Profile
Monica Budianu MD
Dr. Budianu of Scripps Clinic/Scripps Green Hospital has no relevant financial relationships to disclose.See Profile
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.See Profile
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