Cogan syndrome

INTRODUCTION — 

Cogan syndrome (CS) is a chronic inflammatory disorder that most commonly affects young adults. Clinical hallmarks are interstitial keratitis (IK) and vestibuloauditory dysfunction [1]. Associations between CS and systemic vasculitis, as well as aortitis, also exist [2-4].

The pathophysiology, clinical manifestations, and treatment of CS will be presented here.

PATHOPHYSIOLOGY

Pathogenesis — The mechanisms responsible for the eye and inner ear disease in Cogan syndrome (CS) are unknown. Some evidence suggests that the disease is a result of inner ear autoimmunity. A few patients display reactivity against antigens expressed in the inner ear [5]. These antigens share sequence homology with Ro/SSA autoantigen, laminin, cell density-enhanced protein tyrosine-1 (DEP-1/CD148), connexin 26, and the reovirus III major core protein lambda 1 [6]. In animals, passive transfer of these autoantibodies into mice reproduced features of CS [5].

In addition, antibodies to Hsp-70 have been detected in some patients with CS and other forms of autoimmune sensorineural hearing loss [7].

Potential risk factors

●Viral infection – One-quarter to one-third of patients with CS have an antecedent viral-like illness [2,8,9]. This observation indirectly supports a hypothesis that infection, perhaps from reovirus type III, may be involved in triggering this autoimmune disease through molecular mimicry.

●Tobacco exposure – Cigarette smoking has been identified as a potential trigger [9].

●Checkpoint inhibitors – CS has also been reported in a patient with recurrent melanoma who was treated with nivolumab, a PD1 immune checkpoint inhibitor. [10].

Pathology — Representative findings include the following:

●Temporal bone – Limited autopsy data derived from temporal bone specimens of patients with CS reveal a range of findings, including [11-14]:

•Lymphocyte and plasma cell infiltration of the spiral ligament

•Loss of cochlear neurons

•Endolymphatic hydrops

•Flattened sensory epithelial cells, vacuolization, and other degenerative changes in the organ of Corti

•Extensive new bone formation in the inner ear

•Demyelination and atrophy of the vestibular and cochlear branches of the eighth cranial nerve

•Extension of Reissner's membrane into the scala vestibuli [15]

●Cornea – Histopathologic examination of corneal tissue from patients with interstitial keratitis (IK) reveals lymphocytic and plasma cell infiltration in the deeper layers [14].

●Cardiovascular – In cases with systemic vasculitis, affected vessel walls outside the eye and inner ear show typical histopathologic changes of acute and chronic inflammation depending upon the nature of involvement (Takayasu-like or polyangiitis-like) [2,11,16-19]. (See "Clinical features and diagnosis of Takayasu arteritis".)

Damaged aortic valves in cases of aortitis grossly manifest cusp detachments and outpouchings, fenestrations, thinning, thickening, and retraction [16,17,19,20]. Microscopic examination of affected valvular tissue shows lymphoid cell infiltration, fibrinoid necrosis, and myxomatous degeneration [16,17,19-21].

Despite an association with systemic vasculitis, eye and inner ear specimens from patients with CS generally do not reveal any evidence of vasculitis. However, a single autopsy case reported histopathologic evidence of vasculitis in both the cochlear and vestibular systems [22].

EPIDEMIOLOGY

●Prevalence – The prevalence of Cogan syndrome (CS) is unknown. There is no known sex or racial predominance.

●Incidence – The peak incidence of CS occurs in the third decade of life. In two series, the median age of onset was 22 years (range 5 to 63 years) [2,3]. CS may also occur in children and in older adults [23-25].

CLINICAL FEATURES — 

Cogan syndrome (CS) is equally likely to present with eye or inner ear disease. Fewer than 5 percent of patients initially present with systemic manifestations. In these cases, the diagnosis of CS can only be established after the development of eye or inner ear disease [2,3,9].

Ocular disease

●Interstitial keratitis (IK) – The predominant ocular feature of CS is IK, which refers to inflammation of the cornea, typically causing eye redness, pain, photophobia, and blurred vision. Slit lamp examination commonly demonstrates a patchy, deep, granular corneal infiltrate (image 1).

Cases of early IK may produce a faint peripheral, anterior stromal, subepithelial keratitis [26]; these manifestations may be confused with a viral or chlamydial infection [26]. Rarely, uncontrolled corneal inflammation may lead to neovascularization and corneal clouding, resulting in permanent visual loss [9,27].

Although IK is the classic eye finding, it is not essential for the diagnosis.

●Other ocular manifestations – Ocular inflammation may involve other parts of the eye and may lead to iridocyclitis, conjunctivitis, episcleritis, anterior or posterior scleritis (image 2), retinal vasculitis, choroidal effusion [28], or dacryoadenitis with orbital myositis [3,9,23,29-31].

Retinal vasculitis and posterior scleritis are serious conditions that frequently cause visual impairment; when present, they demand urgent treatment. (See "Scleritis: Treatment", section on 'Treatment' and "Uveitis: Treatment", section on 'Initial treatment'.)

Although IK is the classic eye finding in CS, it is not required for its diagnosis. Approximately 80 percent of patients with CS manifest IK; 23 percent show evidence of ocular inflammation at multiple sites (eg, uveitis, episcleritis, optic neuritis, papilledema); and fewer than 5 percent exhibit other types of ocular inflammation, such as retinal vasculitis, central vein occlusion, vasculitic optic neuropathy, and papilledema in isolation [9].

Inner ear disease

●Vestibular dysfunction – The inner ear manifestations of CS are characterized by Ménière-like attacks consisting of hearing loss, vertigo, ataxia, nausea, vomiting, and tinnitus [32]. Vestibular dysfunction may also cause oscillopsia, which is the perception of objects jiggling back and forth after abruptly turning the head to one side or the other. Caloric testing often reveals absent vestibular function. (See "Evaluation of the patient with vertigo", section on 'Other vestibular signs'.)

Some patients with CS may present with inner ear disease prior to the development of the ocular manifestations, typically within a couple of years. Thus, such patients may initially be thought to have autoimmune inner ear disease.

●Sensorineural hearing loss – Recurrent episodes of inner ear disease frequently result in profound hearing loss. In a retrospective series of 60 patients from one center, hearing loss was typically sudden, bilateral, fluctuating, and progressive, resulting in complete hearing loss in 73 of 120 ears [9]. Hearing loss in both ears was noted at some point in all patients. Two smaller studies both found bilateral deafness in approximately two-thirds of patients [2,3]. In our experience, the hearing loss is incremental with periods of relatively stable but reduced hearing between episodes of sudden down-fluctuations in hearing that may respond to steroids.

●Cochlear hydrops – Recurrent episodes of inner ear disease may also result in cochlear hydrops, which is an increase in fluid in the inner ear that causes a loss of hearing in the low to mid frequencies; cochlear hydrops is often accompanied by a sense of ear fullness or the perception of altered pitch that sound is a different pitch in one ear [2,22]. Cochlear hydrops is a noninflammatory cause of hearing fluctuations that may be difficult to distinguish from inflammatory sensorineural hearing loss from active CS [33].

Systemic vasculitis

●Aortitis – Aortitis may develop within weeks to years of disease onset and has been described in approximately 10 percent of patients [2,3,32]. It may cause proximal aorta dilation, aortic valvular regurgitation, ostial coronary artery disease, and thoracoabdominal aortic aneurysms [16,17,32,34-36]. Coronary arteritis has also been described [3,18,33].

The large-vessel vasculitis associated with CS most often resembles Takayasu arteritis, causing an occlusion of the aortic arch vessels with resultant upper and/or lower limb claudication or renal artery stenosis [16,18,37,38]. (See "Clinical features and diagnosis of Takayasu arteritis".)

●Other forms of vasculitis – Rarely, CS may present with cutaneous manifestations of a small- or medium-vessel vasculitis, leading to purpura or pyoderma gangrenosum-like lesions, which may occur with or without aortitis [39]. Other rarely reported manifestations of small- or medium-vessel vasculitis include aural chondritis [9], vasculitic gastric ulcer [18], abdominal pain secondary to mesenteric insufficiency [40], urticarial vasculitis [41], spontaneous rupture of a renal artery [40], and renal artery stenosis [38].

Other findings — Nonspecific systemic manifestations of CS include fever, fatigue, weight loss, lymphadenopathy, hepatomegaly, hepatitis, splenomegaly, pulmonary nodules, pericarditis, abdominal pain, arthralgia, arthritis, myalgia, and urticaria [4,9,31,32]. The disorder has also been described in patients with inflammatory bowel disease [40,42,43].

DIAGNOSIS

In whom to suspect — Most commonly, we consider Cogan syndrome (CS) in patients who have already been diagnosed as having a key component of this disease by another specialist, namely ocular inflammation, particularly interstitial keratitis (IK), or steroid-responsive vestibular dysfunction or sensorineural hearing loss.

We would also consider CS in a patient with or without aortitis and any two of the following features:

●Ocular inflammation (eg, red eye associated with pain, tearing, decreased visual acuity)

●Sensorineural hearing loss (eg, hearing loss that is bilateral, asymmetric, and fluctuating or progressive and responsive to steroids)

●Meniere disease or vertigo.

Patients with any of the above manifestations should undergo an evaluation as outlined in the next section.

Evaluation — Evaluation of the patient with possible CS requires a multidisciplinary approach, typically including a rheumatologist, an ophthalmologist, an audiologist, and an otolaryngologist with expertise in hearing loss.

●Referral for eye examination by an ophthalmologist – Slit lamp examination is used to establish the presence of IK, which is present in about 80 percent of patients with CS but may be subtle [9].

A complete ophthalmologic examination may also identify other causes of ocular inflammation (eg, scleritis, uveitis). The approach to the patient who potentially has ocular inflammation is discussed elsewhere. (See "The red eye: Evaluation and management", section on 'Eye examination'.)

●Referral for audiometry – Audiometry will differentiate between conductive hearing loss and sensorineural hearing loss, which in CS preferentially affects the low- and high-range frequencies (whereas presbycusis is characterized by bilateral hearing loss only in the high-range frequencies); it will also quantify the extent of any problems with speech discrimination (figure 1A-B). In one preliminary study, at least 30 percent of patients had a pure-tone audiometry threshold of greater than or equal to 60 dB, a threshold value indicative of moderately severe hearing loss [4]. The use of audiometry to assess hearing loss is discussed elsewhere. (See "Evaluation of hearing loss in adults", section on 'Formal audiologic assessment'.)

●Consider referral for vestibular evaluation – Formal vestibular testing may not be necessary if vestibular dysfunction can be established based on the presence of symptoms (eg, episodic vertigo). The evaluation of vestibular dysfunction is discussed elsewhere. (See "Evaluation of the patient with vertigo", section on 'Other tests'.)

●Careful physical examination – The history and physical examination may, in addition to eliciting findings of eye inflammation, hearing loss, and vestibular dysfunction, identify signs and symptoms of chronic inflammation in other organ systems, especially systemic vasculitis. While aortitis is most commonly associated with CS and is diagnosed by imaging, features of a small- and/or medium-vessel vasculitis may be evident on skin examination. The evaluation of a patient suspected of having aortitis or other forms of vasculitis is discussed elsewhere. (See "Clinical features and diagnosis of Takayasu arteritis", section on 'Clinical features' and "Overview of and approach to the vasculitides in adults", section on 'Diagnostic approach'.)

Establishing the diagnosis — We diagnose CS in any patient who develops both IK and vestibular dysfunction within a two-year period, regardless of the patient's age.

CS may also be diagnosed in patients presenting with various non-IK forms of ocular inflammation in combination with steroid-responsive inner ear disease. In such cases, CS should be diagnosed after excluding other possible diagnoses (see 'Differential diagnosis' below). CS does not usually apply when ocular inflammatory disease occurs alone, more than two years prior to the diagnosis of inner ear disease, or in association with a systemic rheumatologic disease (which represents the majority of patients presenting with ocular inflammation and steroid-responsive inner ear disease).

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of Cogan syndrome (CS) includes diverse conditions that cause similar eye and inner ear manifestations (table 1). The differential is often based on whether the patient first presents with ocular or inner ear disease. Findings that commonly raise the possibility of CS include the following:

Ocular disease — Keratitis, uveitis, and scleritis may all present with red eye, and varying degrees of pain, photophobia, and decreased vision. Although each has characteristic features, a slit lamp examination by an experienced provider is required for definitive diagnosis.

●Keratitis – Infectious keratitis can be caused by bacteria, viruses, fungi or parasites.

Infectious causes of interstitial keratitis (IK) include congenital syphilis, tuberculosis, chlamydial infection, and viral infection. Infectious agents can be differentiated from CS by serologic testing (eg, fluorescent treponemal antibody absorption [FTA-ABS] test for syphilis), skin tests (eg, tuberculin skin testing), interferon gamma release assays (QuantiFERON TB Gold, T-SPOT), cultures, therapeutic trials of antimicrobial treatment, and characteristic clinical signs (eg, dendritic pattern in herpetic corneal infections). (See "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis", section on 'Late congenital syphilis' and "Tuberculosis and the eye" and "Infectious conjunctivitis".)

●Uveitis – The occurrence of uveitis in particular raises the diagnostic possibility of Behçet syndrome, spondyloarthritis, Crohn disease, sarcoidosis, and Lyme disease. The differential diagnosis and evaluation of patients with uveitis are discussed separately. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Etiology'.)

●Scleritis – Scleritis is associated with multiple rheumatic diseases, especially rheumatoid arthritis and granulomatosis with polyangiitis (table 2). The differential diagnosis and evaluation of patients with scleritis are discussed separately. (See "Clinical manifestations and diagnosis of scleritis", section on 'Systemic disease associations'.)

Inner ear disease

●Meniere disease – Like CS, Meniere disease is associated with vertigo, tinnitus and hearing loss. However, it lacks the ocular inflammation characteristic of CS. Early in the disease course, Meniere disease may appear to be steroid-responsive due to its fluctuating course; however, CS generally affects both ears simultaneously, whereas Meniere disease may be unilateral. (See "Meniere disease: Evaluation, diagnosis, and management", section on 'Diagnosis'.)

●Susac syndrome – CS also must be distinguished from Susac syndrome, which occurs predominately in adults between the ages of 20 and 40 and is characterized by subacute encephalopathy, sensorineural hearing loss, and retinal arteriolar occlusions due to an occlusive nonvasculitic vasculopathy [44]. The major findings in this disorder, which differ from those in CS, include the presence of retinal and neuropsychiatric findings and the absence of IK or other inflammation of the anterior segment of the eye. (See "Primary angiitis of the central nervous system in adults", section on 'Alternative diagnoses'.)

●Presbycusis – Gradual onset of hearing loss is much less likely to be inflammatory in nature, and typically occurs in age-related sensorineural hearing loss.

TREATMENT — 

Therapeutic options for the treatment of Cogan syndrome (CS) include the use of topical agents for limited ocular disease and immunosuppressive therapy for more extensive ocular disease, inner ear involvement, and/or systemic vasculitis.

Systemic vasculitis — Patients with CS who also have evidence of a large-vessel vasculitis (eg, aortitis, bruits, limb claudication) are managed using the same strategies used for Takayasu arteritis. (See "Treatment of Takayasu arteritis", section on 'Pretreatment evaluation'.)

Patients with CS who also have evidence of a medium-vessel vasculitis (eg, mononeuritis multiplex, mesenteric angina, renal infarct, cutaneous ulceration) are managed using the same strategies used for polyarteritis nodosa. (See "Treatment and prognosis of polyarteritis nodosa".)

Patients with CS who also have evidence of a small-vessel vasculitis (eg, purpura) are managed using the same approach as taken for the treatment of a small-vessel vasculitis (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Initial treatment approach'). In the authors' experience, CS is not associated with pulmonary hemorrhage or glomerulonephritis.

Ocular disease — In patients with CS, anterior ocular inflammation and posterior ocular inflammation are treated quite differently. Anterior disease usually responds to topical glucocorticoids, while posterior involvement requires systemic therapy.

●Interstitial keratitis (IK) – Anterior ocular inflammation, such as IK and anterior uveitis, should initially be treated with topical ocular glucocorticoids. Prednisolone acetate at 1% (lower-potency formulations are also frequently adequate) and mydriatics are administered to decrease ocular inflammation and photophobia, prevent synechiae, and relieve ocular discomfort [33,45]. The frequency of administration depends on the severity of the symptoms; the symptoms and signs of IK and anterior uveitis usually improve within three to seven days with topical glucocorticoid therapy [3]. The use of topical agents for anterior ocular inflammation is discussed elsewhere. (See "Uveitis: Treatment", section on 'Initial treatment'.)

Topical therapy alone is adequate to treat IK. Patients with IK who fail to respond to the above regimen should be evaluated and treated for other potential causes of corneal inflammation, particularly chlamydia. A trial of oral doxycycline (200 mg daily for two to three weeks) should be considered in such cases [33,45,46]. Rarely, treatment of IK or anterior uveitis may require systemic glucocorticoid therapy if the above treatments are ineffective after 2 to 2.5 weeks [47]. Topical glucocorticoids do not exacerbate a chlamydial infection as long as the patient is receiving oral tetracycline therapy.

●Other forms of ocular inflammation – The management of other forms of ocular inflammation (eg, scleritis, uveitis) are discussed in detail elsewhere. (See "Scleritis: Treatment", section on 'Treatment' and "Uveitis: Treatment", section on 'Initial treatment'.)

Inner ear disease — We treat any patient newly diagnosed with CS who presents with simultaneous compromise of auditory acuity and vestibular dysfunction with systemic glucocorticoids. However, we also consider systemic glucocorticoids in any patient with CS who presents with sudden, clinically significant hearing loss, either unilateral or bilateral. If possible, the degree of hearing loss should be quantified by audiometry for comparison with subsequent audiograms to allow an assessment of response to steroid treatment. Gradual onset of hearing loss is much less likely to be inflammatory in nature, and typically occurs in age-related sensorineural hearing loss.

Glucocorticoids for all patients — For initial therapy, we suggest prednisone (1 to 2 mg/kg daily) to produce a short period of intense immunosuppression [3,4,8,45,48]. We initially divide the dose of prednisone into a twice-daily administration; with clinical improvement, the dose may be consolidated to a single morning administration [33,45].

Subjective hearing improvement and decreased hearing thresholds after two to three weeks of high-dose therapy warrant gradual tapering of the dose over the next four to eight weeks. However, reductions in the glucocorticoid dose are contingent upon stable auditory acuity and vestibular function [45].

Decreases in hearing are suspected to be inflammatory in nature if they occur suddenly or subacutely in the early and intermediate course of CS. These should be documented by audiometry and should be treated with prednisone (0.5 to 2.0 mg/kg daily); the dose chosen depends upon the severity of the change and upon the dose of prednisone at which the hearing loss occurred. Some patients may require long-term glucocorticoid therapy because of recurrent hearing loss during attempts to taper the prednisone dose (figure 1A-B) [33].

Intratympanic glucocorticoids may be effective in some patients with idiopathic sensorineural hearing loss [49]. This approach can be considered, although it is uncertain whether intratympanic glucocorticoids will benefit patients with CS [49].

Adjunctive immunosuppression for selected patients — The use of glucocorticoid-sparing immunosuppressive therapy should be considered in patients for whom excessive glucocorticoid doses either are required to control hearing loss or result in toxicity [33,45]. In this scenario, we suggest methotrexate (15 to 25 mg weekly); however, azathioprine (1.5 to 2.5 mg/kg daily) may be used if methotrexate is not feasible. The duration of therapy depends upon the response. If the glucocorticoid-sparing therapy stabilizes the hearing loss and allows tapering of the glucocorticoids, we continue such therapy for six to nine months after tapering off the glucocorticoids, if possible. Some patients may require chronic glucocorticoid-sparing therapy.

Alternate agents include cyclophosphamide, tacrolimus, leflunomide, mycophenolate mofetil, and tumor necrosis factor (TNF) inhibitors [8,33,50-55]. Any of these medications may be tried if both methotrexate and azathioprine agents are ineffective.

There has also been anecdotal experience using rituximab and interleukin 1 (IL-1) antagonists in the setting of autoimmune hearing loss [56]. A retrospective study of treatment and outcomes of 60 patients with CS suggested vestibuloauditory responses were better with infliximab compared with other therapies [57]. Infliximab may be more effective than other TNF inhibitors [58].

Additional management considerations — Reduced hearing associated with an upper respiratory infection or menses may be monitored without change in therapy to observe if it will resolve in three to five days, since a noninflammatory down-fluctuation frequently abates within this time frame. If this hearing loss is associated with eye inflammation or other features of active CS, then the reduction in hearing is most likely due to inflammation.

●Cochlear implants – Cochlear implants have been beneficial in patients with CS who have failed to respond to pharmacologic therapy, resulting in severe hearing loss [9,59,60]. Outcomes of Cochlear implants for patients with CS appear to be similar to those receiving Cochlear implants due to nonimmune-mediated hearing loss [60,61]. Functional deterioration of Cochlear implants may occur without evident technical issues and improve with immunosuppressive therapy, implying that ongoing cochlear inflammation is the etiologic factor [62].

●Consider cochlear hydrops – When hearing loss is not believed to be caused by inflammation, auditory acuity should be monitored without change in the prednisone dose.

It is difficult to know whether a fluctuation in hearing is inflammatory or not after several months, since these patients may have hearing loss due to cochlear hydrops resulting from damage. The lack of response to steroids and the waxing and waning of hearing over a matter of days are suggestive of cochlear hydrops. An inflammatory basis for the hearing loss may be inferred in some cases by the presence of active ocular inflammation. We treat patients with cochlear hydrops with a low-sodium diet and diuretics (either hydrochlorothiazide 25 mg daily or furosemide 10 or 20 mg daily) [33]. Failure to improve after four to seven days of diuretic therapy, along with the absence of any other explanation for the hearing loss (such as an upper respiratory tract infection), justifies a trial of an increased dose of prednisone [33] as discussed above.

Isolated vestibular dysfunction

●Acute vestibular dysfunction – We suggest treating acute vestibular dysfunction with antihistamines (such as meclizine hydrochloride 12.5 to 25 mg every 6 to 12 hours) as well as bedrest. Benzodiazepines (such as diazepam, 2 to 10 mg four times daily) may be used for patients who cannot tolerate antihistamines. The management of vertigo is discussed in greater detail elsewhere. (See "Treatment of vertigo", section on 'Symptomatic treatment'.)

Recurrent vestibular dysfunction is virtually always accompanied by hearing loss and should be treated as described above, using glucocorticoids and, if needed, glucocorticoid-sparing therapy.

●Recurrent vestibular dysfunction – Significant recurrent vestibular dysfunction without concomitant hearing loss is unusual and should be initially treated symptomatically with antihistamines or benzodiazepines, as discussed above. A trial of glucocorticoids should be considered later if this treatment fails. The authors recommend prednisone 40 mg for five days, followed by a 10 mg taper every 48 hours to 0. Long-term glucocorticoid therapy has generally not been required to control recurrent vestibular dysfunction.

●Chronic vestibular dysfunction – Chronic vestibular dysfunction occurs in a few patients with CS and can be treated with antihistamines, benzodiazepines, and vestibular therapy, which includes exercise activities aimed at maximizing central nervous system compensation for vestibular dysfunction [2,8,9,63]. Vestibular rehabilitation (VR) is a valuable treatment option for chronic symptoms of vertigo or disequilibrium from inner ear disease. VR is a series of exercises involving the head, eye, trunk, and neck movements. They are used to assess balance function and stimulate the vestibular system, which in turn, promotes the visual-vestibular connections that improve balance. In a meta-analysis of Meniere disease, VR was able to improve the quality of life in patients with vestibular dysfunction similar to that found in CS [64]. VR is discussed in greater detail elsewhere. (See "Treatment of vertigo", section on 'Vestibular rehabilitation'.)

PROGNOSIS — 

The disease course of Cogan syndrome (CS) is typically characterized by multiple relapses of inflammatory eye disease and inner ear disease, or both, although some may exhibit a monophasic illness and fewer yet display persistently active disease. In a retrospective review of 60 patients with CS who had received their care at the Mayo Clinic between 1940 and 2002, progression to complete hearing loss was noted in both ears and in one ear in 52 and 18 percent of cases, respectively [9]. The outcomes of the ocular manifestations of CS depend on the type of inflammatory eye disease. However, in this study, the vast majority of patients had normal or near normal vision at the final follow-up [9].

The prognosis of CS appears to have improved with more aggressive use of immunosuppressive drugs and biologic agents. For comparison, a retrospective study of 62 patients with CS that came from two nationwide networks in France (n = 40) and were combined with case reports reported in the literature between 2004 and 2015 (n = 22) showed lower relapse rates (13 and 31 percent of patients relapsed at 5 and 10 years, respectively) than the relapse rates from the patients in the Mayo Clinic study (78 percent relapsed during an average of 7.1 years of follow-up) [57]. Both groups of patients were uniformly treated with high doses of glucocorticoids at initial presentation and during the subsequent clinical course. However, the patients from the French study had greater use of immunosuppressive agents compared with those managed at the Mayo Clinic; 10 of 62 patients in the French study were treated with infliximab, which was only approved for use in late 1998. Caution must be exercised in interpreting these apparent differences in relapse rates between the two studies since these two groups of patients, which were studied over nonoverlapping time periods, may not be strictly comparable in terms of clinical features and disease severity.

Premature death is not a usual feature of CS. When deaths occur in this setting, they mostly result from either a complication of immunosuppressive treatment or an associated systemic vasculitis.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

●Overview – Cogan syndrome (CS) is a chronic inflammatory disorder that most commonly affects young adults. Clinical hallmarks are interstitial keratitis (IK) and vestibuloauditory dysfunction, and associations between CS and systemic vasculitis, as well as aortitis, also exist. There are a range of pathologic findings, most of which reflect immune-mediated injury of the affected tissues; however, despite an association with systemic vasculitis, eye and inner ear specimens of those with CS infrequently reveal any evidence of vasculitis. The underlying mechanisms responsible for the eye and inner ear disease in CS are unknown. (See 'Introduction' above and 'Pathology' above and 'Pathophysiology' above.)

●Epidemiology – The prevalence of CS is unknown, and there is no known sex or racial predominance. The peak incidence occurs in the third decade of life.

●Ocular disease – The predominant ocular feature of CS is IK, which typically causes eye redness, pain, photophobia, and blurred vision. Slit lamp examination commonly demonstrates a patchy, deep, granular corneal infiltrate. IK is not essential for the diagnosis; ocular inflammation may involve other parts of the eye and may lead to iridocyclitis, conjunctivitis, episcleritis, anterior or posterior scleritis, or retinal vasculitis. (See 'Ocular disease' above.)

●Inner ear disease – The inner ear manifestations of CS are Ménière-like attacks consisting of vertigo, ataxia, nausea, vomiting, tinnitus, and hearing loss. Vestibular dysfunction may also cause oscillopsia, and caloric testing often reveals absent vestibular function. Recurrent episodes of inner ear disease frequently result in profound sensorineural hearing loss. Noninflammatory down-fluctuations in hearing may be difficult to distinguish from those of inflammatory origin. If hearing loss is associated with eye inflammation or other features of active CS or does not resolve within three to five days, an inflammatory origin is more likely. (See 'Inner ear disease' above.)

●Other findings – When present, the systemic vasculitis primarily affects the aorta but can be associated with blood vessel inflammation in other distributions. The pattern of vessel involvement may be overlapping. Other systemic manifestations of CS include fever, fatigue, weight loss, lymphadenopathy, hepatomegaly, hepatitis, splenomegaly, pulmonary nodules, pericarditis, abdominal pain, arthralgia, arthritis, myalgia, and urticaria. An association with inflammatory bowel disease has also been observed. (See 'Systemic vasculitis' above and 'Other findings' above.)

●Evaluation and diagnosis – Evaluation of the patient with possible CS requires ophthalmologic examination to establish the presence of IK, scleritis, or episcleritis and to exclude other diseases and ocular pathology; neurologic and otologic examination to establish the presence of vestibuloauditory abnormalities; and rheumatologic examination to seek evidence of systemic vasculitis. We diagnose CS based upon the presence of characteristic inflammatory eye disease and vestibuloauditory dysfunction. The eye and inner ear are nearly equally likely to be the cause of presenting symptoms, while less than 5 percent of patients initially present with systemic manifestations. (See 'Clinical features' above and 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of CS includes diverse conditions that cause similar eye and inner ear manifestations, such as sarcoidosis, granulomatosis with polyangiitis, rheumatoid arthritis, and polyarteritis nodosa. Other diagnostic possibilities include the infectious causes of IK and a syndrome of subacute encephalopathy, sensorineural hearing loss, and retinal arteriolar occlusions in young adults that is due to an occlusive nonvasculitic vasculopathy. (See 'Differential diagnosis' above.)

●Treatment – Treatment options are dictated by the specific disease manifestations experienced by the patient.

•Systemic vasculitis – We manage systemic vasculitis using strategies developed to manage analogous forms of vasculitis in other diseases. (See 'Systemic vasculitis' above.)

•Ocular inflammation – We manage anterior ocular inflammation, including IK and anterior uveitis, with topical prednisolone acetate at 1% and mydriatics. (See 'Ocular disease' above.)

•Inner ear disease – For patients with newly diagnosed CS who present with acute hearing loss with or without vertigo, we suggest prednisone (1 to 2 mg/kg daily) (Grade 2C). We initially administer the prednisone in divided doses, twice daily, and then consolidate to a single morning administration following clinical improvement and taper over 4 to 8 weeks if patients remain stable. Recurrent episodes are similarly treated.

For patients who require prolonged therapy with glucocorticoids, we suggest methotrexate (15 to 25 mg weekly) (Grade 2C). However, we use azathioprine (1.5 to 2.5 mg/kg daily) when methotrexate is not feasible. Some patients with refractory disease may actually have cochlear hydrops in addition to CS and/or require cochlear implants.

•Vestibular disease – We suggest treating acute vestibular dysfunction with antihistamines (such as meclizine hydrochloride 12.5 to 25 mg every 6 to 12 hours) and bedrest (Grade 2C). We also add vestibular therapy for patients with chronic vestibular dysfunction.

●Prognosis – Most patients with CS will have a relapsing course. The prognosis of CS has likely improved with the routine use of immunosuppressive therapy.